Imidazole derivatives, their preparation and their use as S-adenosylmethionine decarboxylase (=SAMDC) inhibitors

ABSTRACT

Described are compounds of formula I ##STR1## wherein R 1  is hydrogen or hydroxy; 
     R 2 , R 2  &#39; and R 2  &#34; are each independently of the others hydrogen or a substituent other than hydrogen; 
     either 
     R 3  is hydrogen or a substituent other than hydrogen and 
     R 4  is hydrogen or lower alkyl, 
     or 
     R 3  and R 4  together form a divalent radical of the formula --(CH 2 ) n  -- wherein n is 2 or 3; 
     R 5  and R 6  are each independently of the other hydrogen, alkyl or aryl; and 
     either R 7  and R 8  are each hydrogen, or R 7  and R 8  together form a bond; tautomers thereof, provided that at least one tautomerisable group is present; and salts thereof. 
     The compounds inhibit the enzyme S-adenosylmethionine decarboxylase and are suitable, for example, for the treatment of tumours and protozoal infections.

This application has been filed under 35 USC 371 as a National Stageapplication of PCT/EP 96/00143, filed Jan. 15, 1996.

BRIEF DESCRIPTION OF THE INVENTION

The invention relates to novel imidazole derivatives, to tautomersthereof and/or to salts thereof, to a process for the preparation ofthose compounds, to pharmaceutical compositions comprising thosecompounds, and to

a) those compounds for use in, or

b) the use of those compounds for, the therapeutic treatment of thehuman or animal body; and/or to the use of those compounds in thepreparation of pharmaceutical compositions.

BACKGROUND OF THE INVENTION

It is known that inhibition of S-adenosylmethionine decarboxylase can beused for therapeutic purposes. Surprisingly, a novel class of compoundshaving valuable pharmacological properties has now been found.

COMPLETE DESCRIPTION OF THE INVENTION

An imidazole derivative according to the invention is especially acompound of formula I ##STR2## wherein

R₁ is hydrogen or hydroxy;

R₂, R₂ ' and R₂ " are each independently of the others hydrogen or asubstituent other than hydrogen;

either

R₃ is hydrogen or a substituent other than hydrogen and

R₄ is hydrogen or lower alkyl,

or

R₃ and R₄ together form a divalent radical of the formula --(CH₂),--wherein n is 2 or 3;

R₅ and R₆ are each independently of the other hydrogen, alkyl or aryl;and either R₇ and R₈ are each hydrogen, or R₇ and R₈ together form abond; a tautomer thereof, provided that at least one tautomerisablegroup is present; or a salt thereof.

Within the scope of the present Application, the general terms usedhereinbefore and hereinafter have preferably the following meanings(unless indicated otherwise):

The term "lower" denotes a radical having up to and including a maximumof 7 carbon atoms, preferably up to and including a maximum of 4 carbonatoms.

Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, or,preferably, ethyl or, especially, methyl.

A substituent other than hydrogen is especially lower alkyl, halo-loweralkyl having one or more, preferably up to three, halogen atoms,cycloalkyl, aryl-lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy,aryloxy, acyloxy, such as lower alkanoyloxy or arylcarbonyl-oxy,halogen, amino, N-lower alkylamino, N,N-di(lower alkyl)amino, acylamino,such as lower alkanoylamino or arylcarbonylamino, nitro, lower alkanoyl,arylcarbonyl, carboxy, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl,such as 1-aryl-lower alkoxycarbonyl, for example benzyloxycarbonyl,carbamoyl (--CONH₂), N-lower alkylcarbamoyl, N,N-di-(loweralkyl)carbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio,lower alkanesulfonyl, sulfamoyl (--SO₂ NH₂), N-lower alkylsulfamoyl orN,N-di(lower alkyl)sulfamoyl.

Halo-lower alkyl is especially mono-, di- or tri-(halo)-lower alkyl,such as trifluoromethyl.

Halogen is, for example, iodine or, preferably, bromine or, especially,fluorine or chlorine.

Cycloalkyl is preferably C₃ -C₈ cycloalkyl (having from 3 to 8 ringcarbon atoms) and especially C₅ -C₆ cycloalkyl (having 5 or 6 ringcarbon atoms), it being possible for cycloalkyl to be unsubstituted orsubstituted by lower alkyl.

Aryl is preferably an aromatic ring system having from 6 to 12 ringcarbon atoms that is unsubstituted or substituted by one or moresubstituents of any kind selected independently of one another, and isbi- or, preferably, mono-cyclic; especially unsubstituted or substitutedphenyl or naphthyl, such as 1- or 2-naphthyl; suitable substituentsbeing preferably one or more, especially from one to three, moreespecially one or two, radicals selected independently of one anotherfrom the group consisting of lower alkyl, phenyl, naphthyl, such as 1-or 2-naphthyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino,halogen, halo-lower alkyl, such as trifluoromethyl, carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di(loweralkyl)carbamoyl, cyano, lower alkanoyl, phenyl- or naphthyl-carbonyl,lower alkanesulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-loweralkylsulfamoyl. Aryl is especially 1- or 2-naphthyl; or phenyl that isunsubstituted or substituted by one or two radicals selectedindependently of one another from halogen, such as fluorine or chlorine(in each case especially in the p-position), lower alkyl, such as methylor tert-butyl (in each case especially in the p-position), lower alkoxy,such as methoxy, and phenyl.

Aryl-lower alkyl preferably contains an aryl radical as defined aboveand is preferably phenyl-lower alkyl and, especially, benzyl.

Aryl-lower alkoxy preferably contains an aryl radical as defined aboveand is especially phenyl-lower alkoxy, such as benzyloxy.

Lower alkanoyl is especially foiinyl or, more especially, acetyl,propionyl or pivaloyl.

Lower alkanoyloxy is especially acetoxy, propionyloxy or pivaloyloxy.

Arylcarbonyl preferably contains an aryl radical as defined above andis, for example, benzoyl or 1- or 2-naphthoyl, each of which isunsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,halogen or by halo-lower alkyl, such as trifluoromethyl.

Lower alkanesulfonyl (lower alkyl--SO₂ --) is preferably methane- orethane-sulfonyl.

Alkyl is a hydrocarbon radical having preferably up to a maximum of 20carbon atoms that is unbranched or has one or more branches, such asdodecyl, for example 1-(n-dodecyl), decyl, for example 1-(n-decyl),nonyl, for example 1-(n-nonyl), octyl, for example 1-(n-octyl), or,preferably, lower alkyl, such as, especially, methyl or, moreespecially, ethyl.

While the other radicals have the meanings given at each of thedefinition levels mentioned hereinbefore and hereinafter (generallydefined compounds of formula I and preferred compounds of formula I),the following compounds are especially preferred:

a) compounds of formula I wherein RI is hydrogen are preferred to thosewherein R₁ is hydroxy;

b) when R₇ and R₈ are each hydrogen, in preferred compounds of formula IR₅ and R₆ are likewise each hydrogen;

c) compounds of formula I wherein R₃ and R₄ together are --(CH₂)₃ -- or,especially, --(CH₂)₂ -- are preferred to those wherein R₃ is hydrogen ora substituent other than hydrogen and R₄ is hydrogen or lower alkyl.

When tautomerisable groups are present in the compounds of formula I, itis possible (for example depending upon the solvent, pH value oraggregate state) for compounds of formula I (and some precursorsthereof) to be in the form of tautomers. For example, in compounds offormula I wherein R₇ and Rs are each hydrogen and the other radicals areas defined, the 4,5-dihydroimidazolyl radical may be in the followingtautomeric forms: ##STR3##

The person skilled in the art is familiar with the occurrence of suchtautomers and of similar tautomers and can therefore easily infer thecorresponding compounds and tautomers. The present invention relatesalso to such tautomers.

If cis/trans-isomerismn is possible and/or centres of asymmetry arepresent, compounds of formula I can be in the form of isomers ormixtures of isomers, for example in the form of mixtures ofdiastereoisomers, enantiomeric mixtures or pure isomers.

On account of their basic properties, salts of compounds of formula Iare especially acid addition salts and, where one or more acid groups(such as --COOH) are present, also internal salts; mixed salts are alsopossible.

Salts are especially the pharmaceutically acceptable, that is to saynon-toxic, salts of compounds of formula I, that is to say especiallythe corresponding acid addition salts with acid anions that aretoxicologically tolerable (at the dose in question).

Such salts are formed, for example, by compounds of formula I withinorganic acids, for example hydrohalic acids, such as hydrochloric acidor hydrobromic acid, sulfuric acid or phosphoric acid, or with organiccarboxylic, sulfonic, sulfo or phosphonic acids or N-substitutedsulfamic acids, for example acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,fumaric acid, lactic acid, malic acid, tartaric acid, gluconic acid,glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid or isonicotinic acid, also with amino acids, such as the 20 a-aminoacids involved in the synthesis of proteins in nature, for exampleglutamic acid or aspartic acid, and with methanesulfonic acid,ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonicacid, benzenesulfonic acid, 4-methylbenzenesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (withthe formation of cyclamates), or with other acidic organic compounds,such as ascorbic acid. Carbonates or hydrogen carbonates are alsopossible.

The mixed salts include, for example, salts of compounds of formula Iwith di- or trivalent acids that have acidic radicals with differentdissociation constants, such as citric acid or phosphoric acid, one ortwo protons of those acids, for example, being replaced by cations, suchas alkali metal cations, for example Na⁺ or K⁺, so that thecorresponding salts contain, in addition to the compound of formula Iand the corresponding acid anions, also the corresponding cations.

Internal salts also may be in the form of mixed salts.

The terms "compounds" and "salts" expressly include also individualcompounds or individual salts.

For isolation or purification it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable, non-toxic salts areused therapeutically, and those salts are therefore preferred.

The compounds according to the invention have valuable, especiallypharmacologically useful, properties. In particular, they have apronounced, specific inhibitory action on the enzymeS-adenosylmethionine decarboxylase (SAMDC). SAMDC, as a key enzyme,plays an important role in polyamine synthesis, which takes place invirtually all mammalian cells, including human cells. SAMDC regulatesthe concentration of polyamines in the cell. Inhibition of the enzymeSAMDC results in a reduction in the polyamine concentration. Since areduction in the polyamine concentration causes inhibition of cellgrowth, it is possible by administering SAMDC-inhibiting substances toinhibit the growth of both eukaryotic and prokaryotic cells and even tokill cells or inhibit the onset of cell differentiation. For example, itis possible to control tumors, for example in models, such as tumorsproduced by syngenic transplantation of tumor cells. Syngenictransplantation means transplantation within a strain of individualsthat are genetically virtually identical.

Inhibition of the enzyme SAMDC can be demonstrated by conventionalmethods (for example by the method of H. G. Williams-Ashmann and A.Schenone, see Biochem. Biophys. Res. Communs. 46, 288 (1972), orpreferably by the method of A. E. Pegg and H. S. Poso, see MethodsEnzymol. 94, 234-239 (1983)). The compounds of the invention have IC₅₀values in the range of from 10⁻⁹ to 10⁻⁴ M, especially from 2×10⁻⁹ to10⁻⁷ M.

A further advantage of the compounds according to the invention is thatthey inhibit diamine oxidase only to a small extent as compared withtheir pronounced inhibitory action on SAMDC and are well tolerated.Inhibition of diamine oxidase is disadvantageous since it can lead tothe accumulation of putrescine and hence to indirect activation of SAMDC(see J. Jaenne and D. R. Morris, Biochem. J. 218, 974 (1984)). The lowdegree of diamine oxidase inhibition can be determined by known methods(see, for example, P. Seppanen, L. Alhonen-Hongistu, K. Kapyaho and J.Janne, Methods Enzymol. 94, 247-253 (1983)).

As polyamine antimetabolites, the compounds of formula I haveantiproliferative properties which can be demonstrated, for example, byidentifying the inhibitory action on the growth of human T24 bladdercell carcinomas. This is demonstrated by incubating the cells in"Eagle's Minimal Essential Medium" (see Eagle, H., Science 130,c1432-1437 (1959)), to which 5% (v/v) fetal calf serum is added, in ahumidified incubator at 37° C. and 5% by volume CO₂ in the air. Thecarcinoma cells (1000-1500; ATCC HB 4) are transferred to 96-wellmicrotitre plates and are incubated overnight under the said conditions.The test compound is added in serial dilutions on day 1. The plates areincubated under the said conditions for 5 days. During that period,control cultures undergo at least 4 cell divisions. After theincubation, the cells are fixed with 3.3% (weight/volume=w/v) aqueousglutaraldehyde solution, washed with water and stained with 0.05% (w/v)aqueous methylene blue solution. After washing, the dye is eluted with3% (w/v) aqueous hydrochloric acid. The optical density (OD) per well,which is directly proportional to the number of cells, is then measuredby means of a photometer (Titertek multiskan) at 665 nm. The IC₅₀ valuesare calculated by means of a computer system using the formula ##EQU1##The IC₅₀ value is defined as the concentration of active ingredient atwhich the number of cells per well at the end of the incubation periodis only 50% of the number of cells in the control cultures.

For compounds of formula I, IC₅₀ values in the range of from 10⁻⁴ to5×10⁻⁷ M, especially in the range of from 10⁻⁵ to 10⁻⁶ M, are obtained.

The tolerability and anti-tumor activity of the compounds of formula Iin vivo can be demonstrated by known methods, for example using themethod of U. Regenass, H. Mett, J. Stanek, M. Muller, D. Kramer and C.W. Porter (see Cancer Res. 54, 3210-3217 (1994)). Briefly, the procedureis as follows: To determine the maximum tolerable dose (MTD), thecompounds according to the invention (for example dissolved in distilledwater/0.9% NaCl) are injected i.p. into three mice per group. The doseis increased until the first animals die within a period of 10 days. Todetermine the anti-tumor activity, for example, small pieces of humanT-24 bladder carcinoma cells (ATCC HTB 4) are cultured and transplantedas xenogenic transplants ("xenografts") into female BALB/c nude mice(Bomholtgarden, Copenhagen, Denmark). The anti-tumor treatment usingcompounds of formula I is started after at least three successivetransplants. Tumor fragments weighing approximately 25 mg aretransplanted into the left flank of the mouse (n=6 per group). Treatmentis started as soon as the tumors have an average tumor volume of from150 to 200 mm³. The growth of the tumors is determined twice weekly bymeasuring mutually perpendicular tumor diameters. The tumor volumes aredetermined in the manner described by U. Regenass, H. Mett, J. Stanek,M. Muller, D. Kramer and C. W. Porter (see Cancer Res. 54 3210-3217(1994)) and are given as relative tumor size (i.e. increase in tumorvolume relative to the tumor volume at the beginning of treatment) inT/C % (percent treated/control). The test compounds are dissolved indistilled water and diluted with 3 volumes of 0.9% (w/v) NaCl in water.

Values found for MTD are especially in the region of more than 200 mg/kgp.o. for example more than 500 mg/kg p.o.; or more than 50 mg/kg i.p.,for example approximately 125 mg/kg i.p.. In the determination of theactivity against tumors, dose-dependent inhibition of tumor growth onadministration of compounds of formula I is found; in particular, in thecase of p.o. administration marked reductions in tumor growth are foundat a dose of as little as approximately 5 mg/kg, and in the case of i.p.administration very marked reductions in tumor growth are found at thelowest dose used (3.13 mg/kg), with preferred T/C values of less than60%.

It is also possible to demonstrate the effectiveness of the compounds offormula I against trypanosomes using test systems known per se (see, forexample, Brun, R. and Kunz, C., Acta Tropica 46 361-368 (1989)).

The compounds also exhibit good to very good plasma levels whenadministered p.o. (for example to mice).

When partitioned between octanol and water (log P determination), thecompounds of formula I exhibit good lipophilicity.

Accordingly, the compounds of formula I can be used, for example, in thetreatment of benign and malignant tumors. They are able to bring aboutthe regression of tumors and also to prevent the spread of tumor cellsand the growth of micrometastases. Moreover, they are beneficial, forexample, in the treatment of protozoal infections, such astrypanosomiasis, malaria, or pulmonary inflammation caused byPneumocystis carinii.

The corresponding diseases, especially tumor diseases, in warm-bloodedanimals, especially in mammalian domestic animals and in humans, can betreated.

As selective SAMDC inhibitors, the compounds of formula I can be usedeither on their own or in combination with other substances havingpharmacological activity, for example in combination with (a) inhibitorsof other enzymes of polyamine biosynthesis, for example ornithinedecarboxylase inhibitors, (b) inhibitors of protein kinase C, (c)inhibitors of tyrosine protein kinase, (d) cytokines, (e) negativegrowth regulators, (f) aromatase inhibitors, (g) anti-oestrogens or (h)conventional cytostatic or also cytotoxic active ingredients.

Preference is given to a compound of formula I wherein

R₁ is hydroxy or, especially, hydrogen; the radicals R₂, R₂ ' and R₂ "are each independently of the others hydrogen or a substituent selectedfrom lower alkyl, halo-lower alkyl having one or more, preferably up tothree, halogen atoms, such as trifluoromethyl, C₃ -C₈ cycloalkyl,phenyl-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy,phenyloxy, lower alkanoyloxy or benzoyloxy, halogen, amino, N-loweralkylamino, N,N-di(lower alkyl)amino, lower alkanoylamino, benzoylamino,nitro, lower alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl,1-phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di(lower alkyl)carbamoyl, N-phenylcarbamoyl,cyano, mercapto, lower alkylthio, lower alkanesulfonyl, sulfamoyl,N-lower alkylsulfamoyl and N,N-di-(lower alkyl)sulfamoyl;

either

R₃ is hydrogen and

R₄ is hydrogen or lower alkyl

or

R₃ and R₄ together form a divalent radical of the formula --(CH₂)n--wherein n is 2 or 3;

R₅ and R₆ are each independently of the other hydrogen, lower alkyl,such as methyl or ethyl; or phenyl or naphthyl each of which isunsubstituted or mono- to tri-substituted, especially mono- ordi-substituted, such as 1- or 2-naphthyl, wherein the substituents areselected independently of one another from the group consisting of loweralkyl, phenyl, naphthyl, lower alkoxy, hydroxy, lower alkanoyloxy,nitro, amino, halogen, halo-lower alkyl, such as trifluoromethyl,carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di(lower alkyl)carbamoyl, cyano, lower alkanoyl, phenyl- ornaphthylcarbonyl, lower alkanesulfonyl, sulfamoyl, N-loweralkylsulfamoyl and N,N-di-lower alkylsulfamoyl; R₅ preferably beinghydrogen; and

either R₇ and R₈ are each hydrogen, or R₇ and R₈ together form a bond; atautomer thereof, provided that at least one tautomerisable group ispresent; or a salt thereof.

Special preference is given to a compound of formula I wherein R₁ ishydroxy or, especially, hydrogen;

R₂, R₂ ' and R₂ " are each hydrogen;

either

R₃ is hydrogen and

R₄ is hydrogen or lower alkyl, or

R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --;

R₅ is hydrogen, lower alkyl, such as methyl or ethyl; or naphthyl orphenyl each of which is unsubstituted or substituted by from one tothree, especially one or two, radicals selected from lower alkoxy, suchas methoxy, halogen, such as bromine or, especially, chlorine orfluorine, lower alkyl, such as methyl or also tert-butyl, and phenyl;

R₆ is hydrogen; and

either R₇ and R₈ are each hydrogen, or R₇ and R₈ together form a bond; atautomer thereof, provided that at least one tautomerisable group ispresent; or a salt thereof.

Greater preference is given to a compound of formula I wherein

R₁ is hydroxy or, especially, hydrogen;

the radicals R₂, R₂ ' and R₂ " are each hydrogen;

either

R₃ is hydrogen and

R₄ is hydrogen or lower alkyl, or

R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --;

R₅ is hydrogen, lower alkyl, phenyl, 2-, 3- or 4-lower alkoxyphenyl,2,5-di-lower alkoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-loweralkylphenyl, 4-biphenylyl, or 1- or 2-naphthyl;

R₆ is hydrogen; and

either R₇ and R₈ are each hydrogen, or R₇ and R₈ together form a bond;or a salt thereof;

lower alkyl in the mentioned radicals being in each case especiallymethyl or ethyl.

Very great preference is given to a compound of formula I wherein R₁,R₂, R₂ ' and R₂ " are each hydrogen;

either

R₃ is hydrogen and

R₄ is hydrogen or methyl, or

R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --;

R₅ is hydrogen, ethyl, phenyl, 2-, 3- or 4-methoxyphenyl,2,5-dimethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,4-biphenylyl or 2-naphthyl;

R₆ is hydrogen; and

either R₇ and R₈ are each hydrogen, or R₇ and R₈ together form a bond;or a salt thereof.

Very great preference is given also to a compound of formula I wherein

R₁, R₂, R₂ ' and R₂ " are each hydrogen;

R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --;

R₅ is 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4-dimethylphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl or3,5-di(tert-butyl)phenyl;

R₆ is hydrogen; and

R₇ and R₈ together form a bond; or a salt thereof.

The invention relates especially to the specific compounds described inthe Examples, or salts thereof.

The compounds of formula I can be prepared in accordance with methodsknown per se, for example by

a) reacting a compound of formula II ##STR4## wherein W₁ is functionallymodified carboxy and the other radicals are as defined for compounds offormula I, or a salt thereof, with hydroxylamine or ammonia of formulaIII

    R.sub.1 --NH.sub.2                                         (III),

wherein R₁ is hydrogen or hydroxy, or with a salt thereof, functionalgroups in the starting materials that are not intended to participate inthe reaction being, if necessary, in protected form, and removing anyprotecting groups that are present; or

b) reacting a hydroxyimino compound of formula IV ##STR5## wherein theradicals are as defined for compounds of formula I, or a salt thereof,with an aminoimidazole of formula V ##STR6## wherein the radicals are asdefined for compounds of formula I, or with a salt thereof, functionalgroups in the starting materials that are not intended to participate inthe reaction being, if necessary, in protected form, and removing anyprotecting groups that are present; or

c) for the preparation of a compound of formula I wherein R₁ is hydrogenand the other radicals are as defined, reacting an oxo compound offormula VI ##STR7## or a reactive derivative thereof, wherein theradicals are as defined for compounds of formula I, or a salt thereof,with an aminoimidazole of formula V ##STR8## wherein the radicals are asdefined for compounds of formula I, or with a salt thereof, functionalgroups in the starting materials that are not intended to participate inthe reaction being, if necessary, in protected form, and removing anyprotecting groups that are present;

and, if desired, converting a compound of formula I obtained accordingto one of processes a), b) or c) into a different compound of formula I,if desired converting a resulting salt of a compound of formula I intothe free compound, if desired converting into a salt a free compound offormula I having salt-forming properties that has been obtained directlyor according to the last-mentioned step from a different salt, and/or,if desired, separating a resulting mixture of isomers of compounds offormula I into individual isomers.

DETAILED DESCRIPTION OF THE PROCESS

In the following detailed description of the preferred processconditions, the radicals R₁, R₂, R₂ ', R₂ ", R₃, R₄, R₅, R₆, R₇ and R₈in starting materials, intermediates and end products are each asdefined for compounds of formula I, unless indicated otherwise.

Process a): Conversion of a cyano group into a hydroxyamidino or amidinogroup

In an intermediate of formula II, WI is functionally modified carboxy,preferably imino-alkoxycarbonyl, imino-alkanethiolcarbonyl (bothespecially in salt form) or, especially, cyano.

In the preparation of amidines of formula I (R₁ =H or OH), the group W₁in a compound of formula II may be, for example: an acid addition saltof an imino-lower alkyl ester (which corresponds to an imino-lower alkylether) or of an imino-lower alkanethiol ester, for example having theradical --C(═NH)--OCH₅.HCl or --C(═NH)--SC₂ H₅.HCl. Cyano is, however,preferred.

Reaction of an imino-(lower)alkyl ester or imino-(lower)alkanethiolester of formula II (in the form of a salt) with ammonia yields acompound of formula I that contains an amidino group (R₁ =H).Preferably, cyano compounds of formula II are converted, for example, byreaction with an alkali metal amide, such as KNH₂, into thecorresponding amidino compounds of formula I (R₁ =H).

N-Hydroxyamidino compounds of formula I (R₁ =OH) can be prepared in ananalogous manner, for example by reacting an imino-(lower)alkyl ester orimino-(lower)alkanethiol ester of formula II (in the form of a salt)with hydroxylamine or a salt thereof.

Preferably, cyano compounds of formula II are converted into thecorresponding amidino (R₁ =H) or, especially, N-hydroxyamidino compounds(R₁ =OH) of formula I with ammonia or, especially, hydroxylamine offormula III, or salts thereof, for example by reaction in the presenceof a base, such as a metal alcoholate, for example the metal alcoholateof a lower alkanol, such as methanol or ethanol, or a metal hydrogencarbonate or, especially, a metal carbonate, preferably a salt of thatkind, "metal" denoting an alkali metal, such as sodium or potassium,such as sodium or potassium methanolate or sodium or potassiumcarbonate. The reaction takes place (i) in the case of metalalcoholates, preferably in the alcohol that matches the metalalcoholate, such as methanol or ethanol, at preferred temperatures offrom 0° to 50° C., especially at room temperature; or (ii) in the caseof metal carbonates (or also metal hydrogen carbonates), in alcohols,such as methanol or ethanol, N,N-di-lower alkyl-alkanoylamides, such asN,N-dimethylformamide, or water, or mixtures thereof, at preferredtemperatures of from 50° C. to the reflux temperature, especially from75° C. to the reflux temperature.

Starting materials of formula II wherein WI isimino-(lower)alkoxycarbonyl are prepared, for example, by acid-catalyzedreaction of compounds of formula II wherein W₁ is cyano with alkanols,especially lower alkanols, for example by reaction with ethanol andhydrochloric acid in, for example, chloroform or diethyl ether. Startingmaterials of formula II wherein W₁ is imino-(lower)alkanethiolcarbonylare obtained, for example, by first of all converting a compound offormula II wherein WI is cyano into the corresponding thiocarboxamide(in which --C(═S)--NH₂ is present instead of W₁) by treatment withhydrogen sulfide (for example in pyridine in the presence of a tertiarynitrogen base, such as triethylamine, at temperatures of from 0° to 50°C., for example at approximately 40° C). The thiocarboxamide can then beS-alkylated, for example with the corresponding (lower) alkyl iodide or,preferably, tri(lower) alkyloxonium tetrafluoroborate, preferably undera protective gas, such as argon, in an inert polar solvent, such as achlorinated hydrocarbon, for example methylene chloride, at preferredtemperatures of from 0° to 50° C., especially at approximately roomtemperature, and thus converted into the imino-(lower) alkanethiol esterhydroiodide (--C(═NH)--S--alkyl--HI) or imino-(lower) alkanethiol estertetrafluoroborate, respectively.

Compounds of formula II wherein W₁ is cyano can be prepared, forexample, by reacting a compound of formula VII ##STR9## wherein CW₂ W₃is free or functionally modified or protected carbonyl, with anaminoimidazole of formula V ##STR10## wherein the radicals are asdefined above (under processes b) and c)).

Functionally modified or protected carbonyl is, for example: di-loweralkoxymethylene (W₂ and W₃ are each lower alkoxy), C₁ -C₂alkylenedioxymethylene (W₂ and W₃ together are C₁ -C₂ alkylenedioxy),di-lower alkylthiomethylene (W₂ and W₃ are each lower alkylthio), C₁ -C₂alkylenedithiomethylene (W₂ and W₃ together are C₁ -C₂ alkylenedithio)or, especially, hydroxyiminomethylene. (W₂ and W₃ together are ═N--OH).

In free carbonyl, which (together with hydroxyiminomethylene) ispreferred, W₂ and W₃ together are oxo (═O).

The reaction takes place under the conditions known per se for thereaction of carbonyl derivatives with amino compounds, especially withacid catalysis, preferably analogously to the conditions mentioned underprocesses b) and c) for the reaction of compounds of formula IV and VI,respectively, with compounds of formula V.

Compounds of formula VII are known or can be prepared in accordance withprocesses known per se (see, for example, Coll. Czechoslov. Chem.Commun. 43, 3227 (1978)).

For example, compounds of formula VII wherein CW₂ W₃ is carbonyl and theother radicals are as defined for compounds of formula I can be obtainedfrom compounds of formula VIII ##STR11## wherein W₂ and W₃ together arecarbonyl and W₄ is halogen, especially bromine, or protected amino, forexample acetylamino, for example by reaction with copper(I) cyanide (inthe case of bromo) or by removal of the acetyl protecting group,diazotisation and reaction with copper(I) cyanide (in the case ofacetylamino).

Compounds of formula VII wherein the group CW₂ W₃ is carbonyl can alsobe prepared by oxidation, for example with chromium trioxide (CrO₃),from the corresponding compounds of formula VIIIa ##STR12## wherein W₄ 'is cyano or halogen, especially bromine, or protected amino, for exampleacetylamino, and when W₄ ' is not cyano but one of the other radicalsmentioned above, the conversion into a cyano group is carried outanalogously to the procedure described above when using compounds offormula VIII.

The corresponding hydroxyimino compounds of formula VII (W₂ and W₃together are ═N--OH) can then be prepared therefrom by subsequentreaction with hydroxylamine (in free form or in the form of a salt)under customary conditions for the reaction of carbonyl groups withnitrogen bases. In the reaction, an oxo compound of formula VII (W₂ andW₃ =oxo) is reacted with hydroxylamine, which is preferably introducedin an equimolar amount or in an excess, preferably an up to ten-foldexcess, relative to the starting material of formula VII, or with a saltthereof, preferably a salt with an inorganic acid, for example ahydrohalic acid, such as hydrofluoric acid, hydrogen chloride, hydrogenbromide or hydrogen iodide, especially hydrogen chloride, with sulfuricacid or a hydrogen sulfate, such as an alkali metal hydrogen sulfate,for example sodium hydrogen sulfate, with phosphoric acid, a hydrogenphosphate or a dihydrogen phosphate, for example an alkali metalhydrogen phosphate or dihydrogen phosphate, such as sodium hydrogenphosphate, disodium hydrogen phosphate, potassium hydrogen phosphate ordipotassium hydrogen phosphate, or a salt with an organic acid, forexample with a carboxylic acid, such as a lower alkanecarboxylic acidthat is unsubstituted or substituted in the lower alkyl moiety,preferably by halogen, such as fluorine, chlorine or iodine, for exampleacetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- ortrichloro-acetic acid, or with a sulfonic acid, such as a loweralkanesulfonic acid, for example methanesulfonic acid, ethanesulfonicacid or ethanedisulfonic acid, or with an arylsulfonic acid, such asbenzene- or naphthalene-sulfonic acid or naphthalene-1,5-disulfonicacid, or a double salt, such as Zn(NH₂ OH)₂ Cl₂ (Crismer's reagent); oris reacted with hydroxylamine prepared in situ, for example from analcoholic solution of nitric oxide and a tin(II) salt, such asSn(II)Cl₂, in the presence of copper salts, or from the potassium saltof N,O-bis trimethyl-silyl!hydroxylamine (prepared from (H₃ C)₃Si--NH--O--Si(CH₃)₃ and potassium hydride in tetrahydrofuran, withsubsequent freeing of the potassium salt of the compound of formula VIIwith an acid, for example ammonium chloride); the reaction being carriedout in water (in the presence or absence of surfactants), in an aqueoussolvent mixture, such as a mixture of water with one or more alcohols,for example methanol or ethanol, di-lower alkyl sulfoxides, such asdimethyl sulfoxide, or di-lower alkyl-lower alkanoylamides, such asdimethylformamide; in organic solvents, such as alcohols, for examplemethanol or ethanol, di-lower alkyl sulfoxides, such as dimethylsulfoxide, di-lower alkyl-lower alkanoylamides, such asdimethylformamide, or in sufficiently inert nitrites, such asacetonitrile; a mixture of such organic solvents; or in liquid ammonia,preferably in an aqueous-alcoholic solution, such as methanol/water orethanol/water; at temperatures of from -78° C. to the reflux temperatureof the corresponding reaction mixture, preferably from -30° to 100° C.,especially from 5° to 90° C., for example at approximately from 75° to80° C.; under pressures of approximately from 1 to 10000 bar,preferably, where hydroxylamine salts are used, under normal pressure;in the absence of a base or preferably, where acid salts ofhydroxylamine are used, with neutralization of the acid with a base,especially with a hydroxide, such as an alkali metal hydroxide, forexample sodium or potassium hydroxide, with a carbonate or hydrogencarbonate, especially an alkali metal or alkaline earth metal carbonateor hydrogen carbonate, for example sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate orbarium carbonate, with a salt of a weak organic acid, especially analkali metal or alkaline earth metal salt of a lower alkanecarboxylicacid, for example sodium acetate or potassium acetate, with organicnitrogen bases, especially a secondary or tertiary amine, for example acyclic 5- or 6-membered secondary or tertiary amine, such as pyrrolidineor pyridine, or with alcoholates, for example alkali metal lower alkylalcoholates, such as sodium or potassium methanolate, ethanolate ortert-butanolate, or with an anion exchanger, the presence of an alkalimetal carbonate being especially preferred; the compound of formula VIIwherein W₂ and W₃ together are hydroxyimino being obtained, preferablydirectly in crystalline form and, where appropriate, afterrecrystallization from solvents or solvent mixtures. Preferably, one ofthe mentioned salts of hydroxylamine, especially the salt of ahydrohalic acid, such as the hydrochloride salt, is reacted in thementioned organic solvents, especially in an alcohol, such as methanolor ethanol, at the mentioned temperatures, especially at approximatelyfrom 75° to 80° C., to yield the corresponding oxime of formula VII,which can be purified or is used further directly.

The other compounds of formula VII, wherein W₂ and W₃ have one of themeanings mentioned above other than oxo or hydroxyimino, can be preparedfrom the oxo or hydroxyimino compounds under customary conditions forthe preparation of ketals, acetals, thioketals or thioacetals.

Compounds of formula VIII and VIIIa are known or can be prepared inaccordance with processes known per se (see, for example, J. Org. Chem.49, 4226 (1984)).

A further, preferred method for the preparation of a compound of formulaII wherein W₁ is cyano, R₇ and R₈ together form a bond and the otherradicals are as defined uses as starting material a guanylhydrazonederivative of formula IX ##STR13## wherein R₂, R₂ ', R₂ ", R₃ and R₄ areas defined for compounds of formula I, which is reacted with a compoundof formula X ##STR14## wherein W₅ is a nucleofugal leaving group and R₅and R₆ are as defined for compounds of formula I, or with a reactivederivative thereof, to form the corresponding compound of formula II.

A nucleofugal leaving group W₅ is especially a leaving group selectedfrom hydroxy esterified by a strong inorganic or organic acid,especially hydroxy esterified by a mineral acid, for example ahydrohalic acid, such as hydrochloric, hydrobromic or also hydriodicacid, or also by a strong organic sulfonic acid, such as a loweralkanesulfonic acid that is unsubstituted or substituted by, forexample, halogen, such as fluorine, or an aromatic sulfonic acid, forexample a benzenesulfonic acid that is unsubstituted or substituted bylower alkyl, such as methyl, halogen, such as bromine, and/or by nitro,such as a methanesulfonic, p-bromotoluenesulfonic or p-toluenesulfonicacid, or hydroxy esterified by hydrazoic acid. The compound in questioncan also be prepared in situ by replacement of a radical W₅, for examplechlorine, by another radical W₅, for example iodine (preferably using analkali metal iodide, such as NaI), followed by further reaction in theresulting reaction mixture.

A reactive derivative of a compound of formula X is especially acorresponding acetal or ketal, especially with lower alkanols, such asmethanol or ethanol. The carbonyl group in formula X is in that case inthe form of a di-lower alkoxymethylene group.

In the case of free compounds of formula X, the reaction preferablytakes place in a suitable polar solvent, such as an alcohol, for examplemethanol or, especially, ethanol, at temperatures of from -10° C. to thereflux temperature, preferably from 0° to 25° C. or at the refluxtemperature. If desired or necessary, a tertiary nitrogen base, forexample a tri-lower alkylamine, such as triethylamine, is added(especially when the compound of formula IX is not used in a molarexcess, for example a two-fold molar excess, relative to the compound offormula X and therefore protons that are released in the reaction can nolonger be bound by the excess of the compound of formula IX). Where areactive derivative of a compound of formula X is used (which ispreferred when R₅ is hydrogen), the reaction takes place especially inan aprotic solvent, for example an N,N-di-lower alkyl-loweralkanoylamide, such as N,N-dimethylformamide or N,N-dimethylacetamide,in the presence of a strong base, especially an alkali metal hydride,such as potassium hydride or, especially, sodium hydride, at preferredtemperatures of from 0° to 100° C., especially from 18° to 60° C.,preferably using a protective gas, such as nitrogen or argon, theradical W₅ being nucleophilically substituted by the 2'-imino nitrogenof the compound of formula IX (indicated by an arrow in formula IX). Theresulting intermediate (containing a reactively derivatized carbonylgroup) is then reacted by treatment with an acid, such as a mineralacid, for example a hydrohalic acid, such as HCl, in aqueous solution atpreferred temperatures of from 60° C. to the reflux temperature, thecorresponding compound of formula II being obtained.

Compounds of formula IX can be prepared in accordance with processesknown per se, especially from compounds of formula VII, as definedabove, by reaction with aminoguanidine, which is preferably used inapproximately equimolar amount or in excess relative to the molar amountof the compound of formula I, especially in an amount that is from 1 to2 times the molar amount. The reaction takes place under conditions thatare customary per se for the reaction of carbonyl groups with nitrogenbases, aminoguanidine preferably being used in the form of the salt ofan acid, for example of a hydrohalic acid, such as hydrogen fluoride,hydrogen chloride, hydrogen bromide or hydrogen iodide, especiallyhydrogen chloride, of sulfuric acid or a hydrogen sulfate, such as analkali metal hydrogen sulfate, for example sodium hydrogen sulfate, ofphosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, forexample an alkali metal hydrogen phosphate or dihydrogen phosphate, suchas sodium hydrogen phosphate, disodium hydrogen phosphate, potassiumhydrogen phosphate or dipotassium hydrogen phosphate, or in the form ofa salt with an organic acid, especially with a carboxylic acid, such asa lower alkanecarboxylic acid that is unsubstituted or substituted inthe lower alkyl moiety, preferably by halogen, such as fluorine,chlorine or iodine, for example acetic acid, chloroacetic acid,dichloroacetic acid, or trifluoro- or trichloro-acetic acid, with lacticacid or with a sulfonic acid, such as a lower alkanesulfonic acid, forexample methanesulfonic acid, ethanesulfonic acid or ethanedisulfonicacid, or an arylsulfonic acid, such as benzene- or naphthalene-sulfonicacid or naphthalene-1,5-disulfonic acid; a salt of a strong acid of thecompound of formula III especially being formed in situ, especially fromthe corresponding salt of a readily volatile weak acid that is capableof being liberated by a strong acid, such as sulfuric acid or, moreespecially, one of the mentioned hydrohalic acids or methanesulfonicacid, such as a lower alkanecarboxylic acid, for example acetic acid, orespecially carbonic acid or hydrogen carbonate, by liberating the weakacid; in water (in the presence or absence of surfactants), in anaqueous solvent mixture, such as a mixture of water with one or morealcohols, for example methanol, ethanol or isopropanol, di-lower alkylsulfoxides, such as dimethyl sulfoxide, or di-lower alkyl-loweralkanoylamides, such as dimethylformamide, organic solvents, such as oneor more alcohols, for example methanol or ethanol, di-lower alkylsulfoxides, such as dimethyl sulfoxide, di-lower alkyl-loweralkanoylamides, such as dimethylformamide, or sufficiently inertnitrites, such as acetonitrile, or a mixture of such organic solvents,preferably in an aqueous-alcoholic solution, such as in water/methanol,water/ethanol or water/isopropanol; preferably at temperatures of from-20° C. to the reflux temperature of the reaction mixture, especially attemperatures of from room temperature to the reflux temperature of thereaction mixture, more especially at approximately the refluxtemperature; the compound of formula VII being obtained directly in freeform or, especially, in the form of a salt, preferably of the acidpresent in the reaction, for example in crystalline form.

Compounds of formula X are known, can be prepared in accordance withprocesses known per se, or are available commercially.

Corresponding reactive derivatives of compounds of formula X are known,are available commercially or can be prepared in accordance withprocesses known per se, for example by reaction of a compound of formulaX with the corresponding alcohol, if necessary in the presence ofdehydrating agents, such as dimethyl sulfide.

Compounds of formula V are known, can be prepared in accordance withprocesses known per se, or are available commercially. They areprepared, for example, as follows:

Compounds of formula V wherein R₇ and R₈ together form a bond areprepared from guanidino compounds of formula XI ##STR15## wherein Q isan aryl-1-alkylidene radical used as a protecting group, especiallybenzylidene or also phenyl-1-ethylidene, by reaction with compounds offormula X ##STR16## wherein W₅ is a nucleofugal leaving group and R₅ andR₆ are as defined for compounds of formula I, or with a reactivederivative thereof.

A nucleofugal leaving group W₅ is especially a leaving group selectedfrom hydroxy esterified by a strong inorganic or organic acid,especially hydroxy esterified by a mineral acid, for example ahydrohalic acid, such as hydrochloric, hydrobromic or also hydriodicacid, or also by a strong organic sulfonic acid, such as a loweralkanesulfonic acid that is unsubstituted or substituted by, forexample, halogen, such as fluorine, or an aromatic sulfonic acid, forexample a benzenesulfonic acid that is unsubstituted or substituted bylower alkyl, such as methyl, halogen, such as bromine, and/or by nitro,such as methanesulfonic acid, p-bromotoluenesulfonic acid orp-toluenesulfonic acid, or hydroxy esterified by hydrazoic acid. Thecompound in question can also be prepared in situ by replacement of aradical W₅, for example chlorine, by a different radical W₅, for exampleiodine (preferably using an alkali metal iodide, such as NaI), followedby further reaction in the resulting reaction mixture.

A reactive derivative of a compound of formula X is especially acorresponding acetal or ketal, especially with lower alkanols, such asmethanol or ethanol. The carbonyl group in formula X is in that case inthe form of, for example, a di-lower alkoxymethylene group.

In the case of free compounds of formula X, the reaction is preferablycarried out in a suitable polar solvent, such as an alcohol, for examplemethanol or, especially, ethanol, at temperatures in the range of from-10° C. to the reflux temperature, preferably from 0° to 20° C. or from20° C. to the reflux temperature. If desired or necessary, a tertiarynitrogen base, for example a tri-lower alkylamine, such astriethylamine, is added (especially when the compound of formula XI isnot used in a molar excess, for example a two-fold molar excess,relative to the compound of formula X and therefore the protons that arereleased in the reaction cannot be bound by the excess of the compoundof formula XI) (see Chem. Ber. 101, 3151-3162 (1968) or J. Het. Chem.11(3), 327-329 (1974)). In order to obtain a free compound of formula V,the protecting group Q (especially benzylidene) is then removed,preferably either with hydrazine (for example in the form of hydrazinehydrate) in a high-boiling alcohol, such as a di-lower alkylene-di-loweralkanol, such as diethylene glycol, at temperatures of from 100° C. tothe reflux temperature, for example from 140° to 170° C., or in thepresence of an acid, such as a mineral acid, for example sulfuric acid,phosphoric acid or, especially, a hydrohalic acid, such as HCl or HBr,in aqueous solution at temperatures of from 50° C. to the boilingtemperature, especially from 100° to 120° C., preferably with thesimultaneous removal by distillation (for example by azeotropicdistillation or steam distillation) of the freed compound of the formulaQ═O, wherein Q is as defined for compounds of formula XI.

Where a reactive derivative of a compound of formula X is used (which ispreferred when R₅ is hydrogen), the reaction is preferably carried outin an aprotic solvent, such as an N,N-di-lower alkyl-loweralkanoylamide, for example N,N-dimethylformamide orN,N-dimethylacetamide, in the presence of a strong base, especially analkali metal hydride, such as potassium hydride or, especially, sodiumhydride, at preferred temperatures of from 0° to 100° C., especiallyfrom 18° to 60° C., preferably using a protective gas, such as nitrogenor argon, the radical W₅ being replaced by the 2'-imino nitrogen of thecompound of formula XI (indicated by an arrow in formula XI). Theresulting intermediate (containing a reactively derivatized carbonylgroup) is then heated by treatment with an acid, such as a mineral acid,for example a hydrogen halide, such as HCl, in aqueous solution atpreferred temperatures of from 60° C. to the reflux temperature (forexample from 60° C. at the start of the reaction, with heating to 120°C. by the end of the reaction), the compound of formula II beingobtained and, where appropriate, the arylalkyl-1-oxo compound Q═O (forexample be:nzaldehyde) that is formed simultaneously during the reactionby the removal of protecting groups being removed by azeotropicdistillation.

Compounds of formula V wherein R₅ is aryl, R₆ is hydrogen and R₇ and R₈together form a bond can also be prepared from corresponding2-amino-3-aroylalkyl-5-lower alkyl-1,2,3-oxazolidine bromides with NH₃(at room temperature or with heating) to yield 2-amino-4-aryl-1-loweralkylcarbonyl-imidazoles, hydrolysis of which (for example withwater/mineral acid, such as HCl, in the presence.or absence of analcohol, such as ethanol), with removal of the lower alkanecarboxylicacid, yields a compound of formula V as last defined (see Hetzheim etal., Chem. Ber. 100, 3418-3426 (1967)).

Compounds of formula V wherein R₅ and R₆ are as defined, and are eachespecially hydrogen, and wherein R₇ and R₈ are each hydrogen areprepared especially from imidazolyl ketones or (preferably) imidazolylthiones of formula XII ##STR17## wherein Z is oxygen or, preferably,sulfur, R₅ and R₆ are as defined for compounds of formula I, and areeach especially hydrogen, and R₇ and R₈ are each hydrogen, by reactionwith a compound of formula XII

    Y--W.sub.6                                                 (XIII),

wherein Y is lower alkyl, especially methyl, and W₆ is a nucleofugalleaving group, especially a leaving group selected from hydroxyesterified by a strong inorganic or organic acid, especially hydroxyesterified by a mineral acid, for example a hydrohalic acid, such ashydrochloric, hydrobromic or also hydriodic acid, or preferably by astrong organic sulfonic acid, such as a lower alkanesulfonic acid thatis unsubstituted or substituted, for example, by halogen, such asfluorine, or especially an aromatic sulfonic acid, for example abenzenesulfonic acid that is unsubstituted or substituted by loweralkyl, such as methyl, halogen, such as bromine, and/or by nitro, suchas methanesulfonic acid, p-bromotoluenesulfonic acid or, especially,p-toluenesulfonic acid, or hydroxy esterified by hydrazoic acid.

The reaction is carried out in suitable solvents or solvent mixtures,such as alcohols, for example a lower alkanol, such as methanol orethanol, at elevated temperature, for example at the reflux temperature,and yields a compound of formula XIV ##STR18## wherein Y is lower alkyland the other radicals are as defined for compounds of formula XII. Thelatter is then converted into a compound of formula Va in the form of anacid addition salt ##STR19## wherein Y and R₅ and R₆ are as defined forcompounds of formula XIV, by reaction with ammonia in aqueous solution,if desired in the presence of a polar organic solvent, such as analcohol, for example methanol, ethanol, isopropanol or a mixturethereof, at preferred temperatures of from 0° C. to the refluxtemperature, especially from room temperature to the reflux temperature(see EP 0 327 919). The compound of formula Va corresponds to a compoundof formula V wherein R₅ and R₆ are as defined, and are each especiallyhydrogen, and R₇ and R₈ are each hydrogen. The corresponding freecompound of formula V can then be obtained from that compound byconverting the salt into the free base or into a different salt,analogously to the method described below for compounds of formula Iunder "Additional process measures", for example by ion exchange on ananion exchanger in the form of the salt of the anion of the acid HY tobe introduced (for example anion exchanger based on astyrene/divinylbenzene polymer with quaternary ammonium groups, with theanion Y⁻ as the counter-ion that is to be introduced).

Other starting materials are known, can be prepared in accordance withprocesses known per se, or are available commercially.

In all starting materials (for example those of formula II and alsoIII), functional groups that are not intended to participate in thereaction may, independently of one another, be in protected form. Ifnecessary, protecting groups can be removed at suitable stages or notuntil the stage of the protected precursors of the end products offormula I.

Where specific protecting groups have already been mentioned, thosegroups are preferred.

The protecting groups for functional groups in starting materials thereaction of which is to be avoided, especially carboxy, amino, hvdroxyand mercapto groups, include especially those protecting groups(conventional protecting groups) that are conventionally employed in thesynthesis of peptide compounds, and also in the synthesis ofcephalosporins and penicillins as well as nucleic acid derivatives andsugars. Those protecting groups may already be present in the precursorsand are intended to protect the functional groups in question againstundesired secondary reactions, such as acylation, etherification,esterification, oxidation, solvolysis, etc.. In some cases theprotecting groups may additionally cause the reactions to proceedselectively, for example stereoselectively. It is characteristic ofprotecting groups that they can be removed easily, that is to saywithout undesired secondary reactions taking place, for example bysolvolysis, reduction, photolysis, and also enzymatically, for exampleunder physiological conditions, and that they are not present in the endproducts.

The protection of functional groups by such protecting groups, theprotecting groups themselves and the reactions for their removal aredescribed, for example, in standard works, such as J.F.W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London and NewYork 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis",Wiley, New York 1981, in "The Peptides"; Vol. 3 (E. Gross and J.Meienhofer, eds.), Academic Press, London and New York 1981, in"Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit,"Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, DeerfieldBeach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate:Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974.

A carboxy group is protected, for example, in the form of an ester groupwhich is selectively removable under mild conditions. A carboxy groupprotected in esterified form is esterified especially by a lower alkylgroup, which is preferably branched in the 1-position of the lower alkylgroup or substituted by suitable substituents in the 1- or 2-position ofthe lower alkyl group.

A protected carboxy group esterified by a lower alkyl group is, forexample, methoxycarbonyl or ethoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group that isbranched in the 1-position of the lower alkyl group is, for example,tert-lower alkoxycarbonyl, e.g. tertbutoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group that issubstituted by suitable substituents in the 1- or 2-position of thelower alkyl group is, for example, 1-aryl-lower alkoxycarbonyl, such asarylmethoxycarbonyl, having one or two aryl radicals, wherein aryl isphenyl that is unsubstituted or mono-, di- or tri-substituted, forexample, by lower alkyl, e.g. tert-lower alkyl, such as tert-butyl,lower alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or bynitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted bythe mentioned substituents, for example 4-nitrobenzyloxycarbonyl or4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl ordiphenylmethoxycarbonyl, substituted by the mentioned substituents, e.g.di(4-methoxyphenyl)methoxycarbonyl, also carboxy esterified by a loweralkyl group, the lower alkyl group being substituted in the 1-or2-position by suitable substituents, such as 1-lower alkoxy-loweralkoxycarbonyl, for example methoxymethoxycarbonyl,1-methoxyethoxycarbonyl or 1-ethoxyethoxy-carbonyl, 1-loweralkylthio-lower alkoxycarbonyl, for example 1-methylthiomethoxy-carbonylor 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroylgroup is benzoyl that is unsubstituted or substituted, for example, byhalogen, such as bromine, e.g. phenacyloxycarbonyl, 2-halo-loweralkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl,2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, as well as2-(trisubstituted silyl)-lower alkoxycarbonyl wherein the substituentsare each independently of the others an aliphatic, araliphatic,cycloaliphatic or aromatic hydrocarbon radical that is unsubstituted orsubstituted, for example, by lower alkyl, lower alkoxy, aryl, halogenand/or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkylor phenyl, each of which is unsubstituted or substituted as above, forexample 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-tri-loweralkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or2-(di-n-butylmethylsilyl)-ethoxycarbonyl, or2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.

A carboxy group can also be protected in the form of an organicsilyloxycarbonyl group. An organic silyloxycarbonyl group is, forexample, a tri-lower alkylsilyloxycarbonyl group, for exampletrimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonylgroup can also be substituted by two lower alkyl groups, e.g. methylgroups, and an amino or carboxy group of a second molecule of thecompound to be protected. Compounds having such protecting groups can beprepared, for example, using corresponding tri-lower alkylhalosilanes,such as tert-butyl-dimethylchlorosilane, as silylating agent.

A carboxy group is also protected in the form of an internal ester witha hydroxy group present at a suitable distance, for example in theγ-position, with respect to the carboxy group, that is to say in theform of a lactone, preferably a γ-lactone.

A protected carboxy group is preferably tert-lower alkoxycarbonyl, forexample tertbutoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,9-fluorenylmethoxy-carbonyl or diphenylmethoxycarbonyl, or a carboxygroup protected in the form of a lactone, especially a γ-lactone.

A protected amino group is protected by an amino-protecting group, forexample in the form of an acylamino, arylmethylamino, etherifiedmercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group, or inthe form of an azido group.

In an acylamino group acyl is, for example, the acyl radical of anorganic carboxylic acid having, for example, up to 18 carbon atoms,especially of a lower alkanecarboxylic acid that is unsubstituted orsubstituted by, for example, halogen or aryl, or of a benzoic acid thatis unsubstituted or substituted by, for example, halogen, lower alkoxyor nitro, or preferably of a carbonic acid semiester. Such acyl groupsare preferably lower alkanoyl, such as formyl, acetyl, propionyl orpivaloyl, halo-lower alkanoyl, for example 2-halo-acetyl, such as2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or2,2,2-trichloro-acetyl, benzoyl that is unsubstituted or substituted by,for example, halogen, lower alkoxy or nitro, such as benzoyl,4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, loweralkoxycarbonyl, lower alkoxycarbonyl that is preferably branched at the1-position of the lower alkyl radical or suitably substituted at the 1-or 2-position, for example tert-lower alkoxycarbonyl, such astert-butoxycarbonyl, 1-aryl-lower alkoxycarbonyl, such asaryl-methoxycarbonyl, having one, two or three aryl radicals which arephenyl that is unsubstituted or mono- or poly-substituted, for example,by lower alkyl, especially tert-lower alkyl, such as tert-butyl, loweralkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or bynitro, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,di-phenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl ordi(4-methoxyphenyl)methoxy-carbonyl, aroylmethoxycarbonyl wherein thearoyl group is preferably benzoyl that is unsubstituted or substitutedby, for example, halogen, such as bromine, for examplephenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example2,2,2-trichloroethoxy-carbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, 2-(trisubstituted silyl)-lower alkoxycarbonyl, forexample 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as2-tri-methylsilylethoxycarbonyl or2-(di-n-butylmethylsilyl)ethoxycarbonyl, or triarylsilyl-loweralkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.

In an arylmethylamino group, for example a mono-, di- or, especially,tri-arylmethylamino group, the aryl radicals are especiallyunsubstituted or substituted phenyl radicals. Such groups are, forexample, benzyl-, diphenylmethyl- or, especially, trityl-amino.

In an etherified mercaptoamino group, the mercapto group is especiallyin the form of substituted arylthio or aryl-lower alkylthio wherein arylis, for example, phenyl that is unsubstituted or substituted, forexample, by lower alkyl, such as methyl or tert-butyl, lower alkoxy,such as methoxy, halogen, such as chlorine, and/or by nitro, for example4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl radical that may be used as anamino-protecting group, acyl is, for example, the corresponding radicalof a lower alkanecarboxylic acid, of a benzoic acid that isunsubstituted or substituted, for example, by lower alkyl, such asmethyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such aschlorine, and/or by nitro, or especially of a carbonic acid semiester,such as a carbonic acid lower alkyl semiester. Corresponding protectinggroups are especially 1-lower alkanoyl-lower alk-1-en-2-yl, for example1-lower alkanoyl-prop-1-en-2-yl, such as 1-acetyl-prop-1-en-2-yl, orlower alkoxycarbonyl-lower alk-1-en-2-yl, for example loweralkoxycarbonyl-prop-1-en-2-yl, such as 1-ethoxycarbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group,for example tri-methylsilylamino or tert-butyl-dimethylsilylamino. It isalso possible for the silicon atom of the silylamino group to besubstituted by only two lower alkyl groups, for example methyl groups,and by the amino group or carboxy group of a second molecule of formulaI. Compounds having such protecting groups may be prepared, for example,using the corresponding chlorosilanes, such astert-butyl-dimethylchlorosilane, as silylating agent.

An amino group can also be protected by conversion into the protonatedform; suitable anions are especially anions of strong inorganic acids,such as sulfuric acid, phosphoric acid or hydrohalic acids, for examplethe chlorine or bromine anion, or of organic sulfonic acids, such asp-toluenesulfonic acid.

Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-loweralkoxycarbonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-loweralk-l-en-2-yl or lower alkoxycarbonyl-lower alk-1-en-2-yl, especiallytert-butoxycarbonyl or benzyloxycarbonyl.

A hydroxy group can be protected, for example, by an acyl group, forexample lower alkanoyl that is unsubstituted or substituted by halogen,such as chlorine, such as acetyl or 2,2-dichloroacetyl, or especially byan acyl radical of a carbonic acid semiester mentioned for protectedamino groups. A hydroxy group can be protected also by tri-loweralkylsilyl, for example trimethylsilyl, triisopropylsilyl ortert-butyl-dimethylsilyl, a readily removable etherifying group, forexample an alkyl group, such as tert-lower alkyl, for exampletert-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, especially2-oxa- or 2-thia-aliphatic or -cycloaliphatic, hydrocarbon radical, forexample 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl,such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl,1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkylhaving from 5 to 7 ring atoms, such as 2-tetrahydrofuryl or2-tetrahydropyranyl, or a corresponding thia analogue, as well as by1-phenyl-lower alkyl, such as benzyl, diphenylmethyl or trityl, it beingpossible for the phenyl radicals to be substituted, for example, byhalogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or by nitro. Apreferred hydroxy-protecting group is, for example,2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxy-carbonyl,diphenylmethoxycarbonyl, benzyl or trityl.

Two hydroxy groups occurring in a molecule, especially adjacent hydroxygroups, or adjacent hydroxy and amino groups can be protected, forexample, by divalent protecting groups, such as a methylene group thatis preferably substituted, for example by one or two lower alkylradicals or by oxo, for example by unsubstituted or substitutedalkylidene, e.g. lower alkylidene, such as isopropylidene,cycloalkylidene, such as cyclohexylidene, a carbonyl group orbenzylidene.

A hydroxy group that is adjacent to a carboxy group can be protected bythe formation of an internal ester (lactone), especially a γ-lactone.

A protected hydroxy group is preferably protected by tri-loweralkylsilyl or in the form of a lactone, especially bytert-butyl-dimethylsilyl or in the form of a γ-lactone.

A mercapto group, for example in cysteine, can be protected especiallyby S-alkylation with unsubstituted or substituted alkyl radicals,silylation, thioacetal formation, S-acylation or by the formation ofasymmetrical disulfide groupings. Preferred mercapto-protecting groupsare, for example, benzyl that is unsubstituted or substituted in thephenyl moiety, for example by methoxy or by nitro, such as4-methoxybenzyl, diphenylmethyl that is unsubstituted or substituted inthe phenyl moiety, for example by methoxy, such asdi(4-methoxyphenyl)methyl, triphenylmethyl, pyridyldiphenylmethyl,trimethylsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl,such as acetamidomethyl, iso-butyrylacetamidomethyl or2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl oralkylaminocarbonyl, especially lower alkylaminocarbonyl, such asethylaminocarbonyl, as well as lower alkylthio, such as S-ethylthio orS-tert-butylthio, or S-sulfo.

The person skilled in the art is familiar with protecting groups thatare suitable for the reaction conditions in question and can thereforeselect them without difficulty.

For the removal of protecting groups, the reaction conditions alreadymentioned specifically are preferably employed.

The removal of protecting groups that are not constituents of thedesired intermediate or, especially, of the end product of formula I iseffected in a manner known per se, for example by means of solvolysis,especially hydrolysis, alcoholysis or acidolysis, or by means ofreduction, especially hydrogenolysis or by means of other reducingagents, as well as photolysis, as appropriate stepwise orsimultaneously, it being possible also to use enzymatic methods. Theremoval of the protecting groups is described, for example, in thestandard works mentioned hereinabove in the section relating toprotecting groups.

For example, protected carboxy, for example lower alkoxycarbonyl(preferably branched in the 1-position), such as tert-loweralkoxycarbonyl, lower alkoxycarbonyl substituted at the 2-position by atrisubstituted silyl group or at the 1-position by lower alkoxy or bylower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonylcan be converted into free carboxy by treatment with a suitable acid,such as formic acid, acetic acid, hydrochloric acid or trifluoroaceticacid, where appropriate with the addition of a nucleophilic compound,such as phenol or anisole. Unsubstituted or substitutedbenzyloxycarbonyl can be freed, for example, by means of hydrogenolysis,that is to say by treatment with hydrogen in the presence of a metallichydrogenation catalyst, such as a palladium catalyst. Moreover, suitablysubstituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can beconverted into free carboxy also by reduction, for example by treatmentwith an alkali metal dithionite, such as sodium dithionite, or with areducing metal, for example zinc, or with a reducing metal salt, such asa chromium(II) salt, for example chromium(II) chloride, customarily inthe presence of a hydrogen-yielding agent that, together with the metal,is capable of producing nascent hydrogen, such as an acid, especially asuitable carboxylic acid, such as an unsubstituted or substituted, forexample hydroxy-substituted, lower alkanecarboxylic acid, for exampleacetic acid, formic acid, glycolic acid, diphenylglycolic acid, lacticacid, mandelic acid, 4-chloromandelic acid or tartaric acid, or in thepresence of an alcohol or thiol, water preferably being added. Bytreatment with a reducing metal or metal salt, as described above,2-halo-lower alkoxycarbonyl (where appropriate after conversion of a2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-loweralkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted intofree carboxy. Aroylmethoxycarbonyl can be cleaved also by treatment witha nucleophilic, preferably salt-forming, reagent, such as sodiumthiophenolate or sodium iodide. The carboxy group can be freed from1-aryl-lower alkoxycarbonyl, for example arylmethoxycarbonyl, such asbenzyloxycarbonyl, also by hydrolysis in the presence of a base, such asan alkali metal hydroxide, for example sodium or potassium hydroxide.2-(Trisubstituted silyl)-lower alkoxycarbonyl, such as 2-tri-loweralkylsilyl-lower alkoxycarbonyl, can also be converted into free carboxyby treatment with a salt of hydrofluoric acid that yields the fluorideanion, such as an alkali metal fluoride, for example sodium or potassiumfluoride, where appropriate in the presence of a macrocyclic polyether("crown ether"), or with a fluoride of an organic quaternary base, suchas a tetra-lower alkylammonium fluoride or tri-lower alkylaryl-loweralkylammonium fluoride, for example tetraethylammonium fluoride ortetrabutylammonium fluoride, in the presence of an aprotic, polarsolvent, such as dimethyl sulfoxide, N,N-dirnethylformamide orN,N-dimethylacetamide. Carboxy protected in the form of organicsilyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for exampletrimethylsilyloxycarbonyl, can be freed in customary manner bysolvolysis, for example by treatment with water, an alcohol or an acid,or, furthermore, a fluoride, as described above. Esterified carboxy canalso be freed enzymatically, for example by means of esterases orsuitable peptidases, for example esterified arginine or lysine, such aslysine methyl ester, by using trypsin. Carboxy protected in the form ofan internal ester, such as in the form of the γ-lactone, can be freed byhydrolysis in the presence of a hydroxide-containing base, such as analkaline earth metal hydroxide or, especially, an alkali metalhydroxide, for example NaOH, KOH or LiOH, more especially LiOH, thecorrespondingly protected hydroxy group being freed at the same time.

A protected amino group is freed in a manner known per se and, accordingto the nature of the protecting groups, in various ways, preferably bymeans of solvolysis or reduction. Lower alkoxycarbonylamino, such astert-butoxycarbonylamino can be cleaved in the presence of acids, forexample mineral acids, e.g. a hydrogen halide, such as hydrogen chlorideor hydrogen bromide, especially hydrogen bromide, or sulfuric orphosphoric acid, preferably hydrogen chloride, or in the presence ofrelatively strong organic acids, such as formic acid, trichloroaceticacid or trifluoroacetic acid, in polar solvents, for example water or acarboxylic acid, such as acetic acid or formic acid, halogenatedhydrocarbons, such as chlorinated lower alkanes, for exampledichloromethane or chloroform, or ethers, preferably cyclic ethers, suchas dioxane, or in organic carboxylic acids that are liquid at thereaction temperature, without solvents, for example in formic acid.2-Halo-lower alkoxycarbonylamino (where appropriate after conversion ofa 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-loweralkoxycarbonylamino group), aroyl-methoxycarbonylamino or4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatmentwith a suitable reducing agent, such as zinc in the presence of asuitable carboxylic acid, such as aqueous acetic acid.Aroylmethoxycarbonylamino can be cleaved also by treatment with anucleophilic, preferably salt-forming, reagent, such as sodiumthiophenolate, and 4-nitrobenzyloxycarbonylamino can be cleaved also bytreatment with an alkali metal dithionite, for example sodiumdithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino,tert-lower alkoxycarbonylamino or 2-(trisubstituted silyl)-loweralkoxycarbonylamino, such as 2-tri-lower alkylsilyl-loweralkoxycarbonylamino, can be cleaved by treatment with a suitable acid,for example formic acid or tri-fluoroacetic acid, for example in ahalogenated hydrocarbon, such as methylene chloride or chloroform(especially when hydroxy protected by benzyl is not to be freed at thesame time), 1-aryl-lower alkoxycarbonylamino, such as unsubstituted orsubstituted benzyloxycarbonylamino, can be cleaved, for example, bymeans of hydrogenolysis, that is to say by treatment with hydrogen inthe presence of a suitable hydrogenation catalyst, such as a palladiumcatalyst, for example bonded to a carrier, such as carbon, preferably inpolar solvents, such as di-lower alkyl-lower alkanoylamides, for exampledimethylformamide, ethers, such as cyclic ethers, for example dioxane,esters, such as lower alkanoic acid lower alkyl esters, for exampleethyl acetate, or alcohols, such as methanol, ethanol or propanol,methanol being especially preferred, preferably approximately at roomtemperature, unsubstituted or substituted triarylmethylamino orformylamino can be cleaved, for example, by treatment with an acid, suchas a mineral acid, for example hydrochloric acid, or an organic acid,for example formic acid, acetic acid or trifluoroacetic acid, whereappropriate in the presence of water, and triphenylaminomethyl can becleaved especially by hydrogenolysis with a noble metal or noble metaloxide as catalyst, such as platinum, palladium or, especially, palladiumhydroxide, the catalyst preferably being bonded to a carrier, such ascarbon, silica gel or aluminum oxide, in inert solvents, such as anether, preferably a lower alkyl-lower alkanoate, such as ethyl acetate,at temperatures of from 20° to 80° C., especially from 50° to 70° C., ifnecessary under elevated pressure, for example approximately from 1 to10 bar, and an amino group protected in the form of silylamino can befreed, for example, by means of hydrolysis or alcoholysis. An aminogroup protected by 2-haloacetyl, for example 2-chloroacetyl, can befreed by treatment with thiourea in the presence of a base, or with athiolate salt, such as an alkali metal thiolate of thiourea, andsubsequent solvolysis, such as alcoholysis or hydrolysis, of theresulting substitution product. An amino group protected by2-(trisubstituted silyl)-lower alkoxycarbonyl, such as 2-tri-loweralkylsilyl-lower alkoxycarbonyl, can be converted into the free aminogroup also by treatment with a salt of hydrofluoric acid that yieldsfluoride anions, as indicated above in connection with the freeing of acorrespondingly protected carboxy group. Likewise, silyl, such astrimethylsilyl or tert-butyldimethylsilyl, bonded directly to a heteroatom, such as nitrogen, can be removed using fluoride ions, preferablywith a fluoride of an organic quaternary nitrogen base, such as atetra-lower alkylammonium fluoride or tri-lower alkylaryl-loweralkylammonium fluoride, for example tetraethylammonium fluoride ortetrabutylammonium fluoride, in the presence of an aprotic, polarsolvent, such as dimethyl sulfoxide or N,N-dimethylacetamide, orespecially an ether, such as tetrahydrofuran, at temperatures of from 0°to 50° C., especially at about room temperature.

Amino protected in the form of an azido group is converted into freeamino, for example, by reduction, for example by catalytic hydrogenationwith hydrogen in the presence of a hydrogenation catalyst, such asplatinum oxide, palladium or Raney nickel, by reduction using mercaptocompounds, such as dithiothreitol or mercaptoethanol, or by treatmentwith zinc in the presence of an acid, such as acetic acid. The catalytichydrogenation is preferably carried out in an inert solvent, such as ahalogenated hydrocarbon, for example methylene chloride, or in water ora mixture of water and an organic solvent, such as an alcohol ordioxane, at approximately from 20° C. to 25° C., or with cooling orheating.

A hydroxy or mercapto group protected by a suitable acyl group, by atri-lower alkylsilyl group or by unsubstituted or substituted1-aryl-(such as 1-phenyl)-lower alkyl is freed analogously to acorrespondingly protected amino group. A hydroxy or mercapto groupprotected by 2,2-dichloroacetyl is freed, for example, by basichydrolysis, and a hydroxy or mercapto group protected by tert-loweralkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbonradical is freed by acidolysis, for example by treatment with a mineralacid or a strong carboxylic acid, for example trifluoroacetic acid. Ahydroxy group protected by benzyloxy is freed, for example, byhydrogenolysis, that is to say by treatment with hydrogen in thepresence of a suitable hydrogenation catalyst, such as a palladiumcatalyst, for example bonded to a carrier, such as carbon, preferably inpolar solvents, such as di-lower alkyl-lower alkanoylamides, for exampledimethylformamide, ethers, such as cyclic ethers, for example dioxane,esters, such as lower alkylalkanoates, for example ethyl acetate, oralcohols, such as methanol, ethanol or propanol, with methanol beingespecially preferred, preferably at about room temperature. Mercaptoprotected by pyridyldiphenylmethyl can be freed, for example, usingmercury(II) salts at pH 2-6 or by zinc/acetic acid or electrolyticreduction; acetamidomethyl and isobutyrylamidomethyl can be removed, forexample, by reaction with mercury(II) salts at pH 2-6;2-chloroacetamidomethyl can be removed, for example, using1-piperidinothiocarboxamide; and S-ethylthio, S-tert-butylthio andS-sulfo can be removed, for example, by thiolysis with thiophenol,thioglycolic acid, sodium thiophenolate or 1,4-dithiothreitol. Twohydroxy groups or adjacent amino and hydroxy groups which are protectedtogether by means of a divalent protecting group, preferably, forexample, by a methylene group mono- or di-substituted by lower alkyl,such as lower alkylidene, for example isopropylidene, cycloalkylidene,for example cyclohexylidene, or benzylidene, can be freed by acidsolvolysis, especially in the presence of a mineral acid or a strongorganic acid. A tri-lower alkylsilyl group is likewise removed byacidolysis, for example by a mineral acid, preferably hydrofluoric acid,or a strong carboxylic acid. Hydroxy can be freed from tri-loweralkylsilyloxy preferably also by treatment with a salt of hydrofluoricacid that yields the fluoride anion, such as an alkali metal fluoride,for example sodium or potassium fluoride, where appropriate in thepresence of a macrocyclic polyether ("crown ether"), or with a fluorideof an organic quaternary base, such as a tetra-lower alkylammoniumfluoride or tri-lower alkylaryl-lower alkylammonium fluoride, forexample tetraethylammonium fluoride or tetrabutylammonium fluoride, inthe presence of an aprotic polar solvent, such as dimethyl sulfoxide orN,N-dimethylacetamide. 2-Halo-lower alkoxycarbonyl is removed using theabove-mentioned reducing agents, for example a reducing metal, such aszinc, reducing metal salts, such as chromium(II) salts, or using sulfurcompounds, for example sodium dithionite or, preferably, sodium sulfideand carbon disulfide. Esterified hydroxy groups, for example loweralkanoyloxy, such as acetyloxy, can also be freed using esterases, andacylated amino can be freed, for example, using suitable peptidases.

The temperatures at which the protected functional groups are freed arepreferably from -80° C. to the boiling temperature of the reactionmixture, especially from -80° to 110° C., more especially from -20° to50° C., for example from 10° to 35° C., such as approximately roomtemperature, or at from 80° C. to the boiling temperature of thereaction mixture in question, for example at approximately 100° C.

When several protected functional groups are present, the protectinggroups may, if desired, be so selected that it is possible to removemore than one such group simultaneously, for example by means ofacidolysis, such as by treatment with trifluoroacetic acid, or by meansof hydrogen and a hydrogenation catalyst, such as a palladium-on-carboncatalyst. Conversely, the groups may also be so selected that they arenot all removed simultaneously but can be removed in a desired sequence,in which case the corresponding intermediates are obtained.

Process b) - Formation of a Schiff's base by reaction of a hydroxyiminocompound with an amino compound

In compounds of formulae IV and V, functional groups that are notintended to participate in the reaction may, if necessary, be inprotected form; protecting groups, processes for their introduction andprocesses for their removal from resulting protected compounds offormula I are analogous to those mentioned in the detailed descriptionof process a).

In the starting materials of formula IV, and hence in the products offormula I, the radical R₁ is preferably hydroxy.

The reaction between compounds of formula IV (hydroxyimino compound) andformula V (aminoimidazole) takes place under conditions that are knownper se, the aminoimidazole of formula V preferably being used in anapproximately equimolar amount or in excess relative to the molar amountof the compound of formula IV, especially in an amount that is from 0.95times to twice the molar amount--in particular, the reaction takes placeunder conditions that are customary for the reaction of carbonylcompounds with nitrogen bases; preferably in the presence of acids, forexample of a hydrohalic acid, such as hydrogen fluoride, hydrogenchloride, hydrogen bromide or hydrogen iodide, especially hydrogenchloride, of sulfuric acid or a hydrogen sulfate, such as an alkalimetal hydrogen sulfate, for example sodium hydrogen sulfate, ofphosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, forexample an alkali metal hydrogen phosphate or dihydrogen phosphate, suchas sodium hydrogen phosphate, disodium hydrogen phosphate, potassiumhydrogen phosphate or dipotassium hydrogen phosphate, or of an organicacid, especially a carboxylic acid, such as a lower alkanecarboxylicacid that is unsubstituted or substituted in the lower alkyl moiety,preferably by halogen, such as fluorine, chlorine or iodine, for exampleacetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- ortrichloroacetic acid, of lactic acid or of a sulfonic acid, such as alower alkanesulfonic acid, for example methanesulfonic acid,ethanesulfonic acid or ethanedisulfonic acid, or an arylsulfonic acid,such as benzene- or naphthalene-sulfonic acid ornaphthalene-1,5-disulfonic acid; there being used especially a strongacid, such as sulfuric acid or, more especially, one of the mentionedhydrohalic acids or methanesulfonic acid; in water (in the presence orabsence of surfactants) or in an aqueous solvent mixture, such as amixture of water with one or more alcohols, for example methanol,ethanol or, especially, isopropanol, or also di-lower alkyl sulfoxides,such as dimethyl sulfoxide, or di-lower alkyl-lower alkanoylamides, suchas dimethylformamide, organic solvents, such as one or more alcohols,for example methanol or ethanol, di-lower alkyl sulfoxides, such asdimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, such asdimethylformamide, or in sufficiently inert nitriles, such asacetonitrile, a mixture of such organic solvents, preferably in anaqueous-alcoholic solution, such as in water/methanol, water/ethanol or,especially, water/isopropanol; preferably at temperatures of from -20°C. to the reflux temperature of the reaction mixture, especially attemperatures of from room temperature to the reflux temperature of thereaction mixture, more especially at approximately from 80° C. to thereflux temperature; the compound of formula I (where appropriate aftercustomary working up) being obtained directly in free form or,especially, in the form of a salt, preferably of the acid present in thereaction, for example in crystalline form. Special preference is givento the reaction of the hydroxyimino compound of formula IV and theaminoimidazole of formula V with aqueous HCl in isopropanol attemperatures of from 80° C. to the reflux temperature (for example nothigher than 120° C.).

The preparation of the starting materials of formula V has already beendescribed in connection with the preparation of starting materials forprocess a).

Hydroxyimino compounds of formula IV are preferably prepared fromcompounds of formula VII, which are described as starting materials inprocess a), wherein W₂ and W₃ are especially together oxo and the otherradicals are as defined therein, different procedures being possible.

For example, compounds of formula IV wherein R₁ is hydrogen and theother radicals are as defined can first be converted into compounds offormula VI ##STR20## wherein the radicals are as defined for compoundsof formula I, by the reaction of cyano compounds of formula VII whereinW₂ and W₃ are especially together oxo, while R₂, R₂ ', R₂ ", R₃ and R₄are as defined for compounds of formula I, with ammonia or with a saltthereof. The reaction is preferably carried out starting from thestarting materials of formula VII by acid-catalysed reaction of thecyano group either

a) with alkanols, especially lower alkanols, for example by reactionwith ethanol and hydrochloric acid in, for example, chloroform ordiethyl ether, via the corresponding compound wherein there is anirnino-(lower) alkoxycarbonyl radical (preferably in salt form) insteadof the cyano group; or

b) preferably by treatment with hydrogen sulfide (for example inpyridine in the presence of a tertiary nitrogen base, such astriethylamine, at temperatures of from 0° to 50° C., for example atapproximately 40° C.) via the corresponding thiocarboxamide (the group--C(═S)--NH₂ is present in formula VII instead of the cyano group),which is then converted into the corresponding compound with animino-(lower) alkanethiolcarbonyl group, preferably the correspondingimino-(lower) alkanethiol ester salt, for example by S-alkylating thethiocarboxamide with the corresponding (lower) alkyl iodide or,preferably, tri-(lower) alkyloxonium tetrafluoroborate, preferably undera protective gas, such as argon, in an inert polar solvent, such as achlorinated hydrocarbon, for example methylene chloride, at preferredtemperatures of from 0° to 50° C., especially at approximately roomtemperature, and thus converting it into the imino-(lower) alkanethiolester hydroiodide (--C(═NH)--S-alkyl.HI) or imino-(lower) alkanethiolester tetrafluoroborate, respectively;

and then, by reaction of the imino-(lower) alkyl ester derivative or theimino-(lower) alkanethiol ester derivative of the compound of formulaVII (in salt form) with ammonia or salts thereof, the correspondingcompound of formula VI containing the amidino group (R₁ =H) is obtained.The reaction with ammonia--with or without previous isolation of theimino-(lower) alkyl ester derivative or imino-(lower) alkanethiol esterderivative of the compound of formula VII (in salt form)--is preferablycarried out in a suitable organic solvent, such as an alcohol, forexample ethanol, at temperatures of from 40° C. to the refluxtemperature, preferably at the reflux temperature, in the presence ofacids, for example a mineral acid, such as sulfuric acid, phosphoricacid or, especially, a hydrohalic acid, such as HCl; in an especiallypreferred form of the process, ammonia is added directly in the form ofthe corresponding salt.

The resulting compound of formula VI is then converted, by conversion ofthe carbonyl group into the hydroxy imino group, into the correspondingcompound of formula IV wherein R₁ is hydrogen and the other radicals areas defined. In the reaction, an oxo compound of formula VI is reactedwith hydroxylamine, which is preferably introduced in an equimolaramount or in an excess, preferably an up to ten-fold excess, relative tothe starting compound of formula VII, or with a salt thereof, preferablya salt with an inorganic acid, for example a hydrohalic acid, such ashydrofluoric acid, hydrogen chloride, hydrogen bromide or hydrogeniodide, especially hydrogen chloride, with sulfuric acid or a hydrogensulfate, such as an alkali metal hydrogen sulfate, for example sodiumhydrogen sulfate, with phosphoric acid, a hydrogen phosphate or adihydrogen phosphate, for example an alkali metal hydrogen phosphate ordihydrogen phosphate, such as sodium hydrogen phosphate, disodiumhydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogenphosphate, or a salt with an organic acid, for example with a carboxylicacid, such as a lower alkanecarboxylic acid that is unsubstituted orsubstituted in the lower alkyl moiety, preferably by halogen, such asfluorine, chlorine or iodine, for example acetic acid, chloroaceticacid, dichloroacetic acid or trifluoro- or tri-chloro-acetic acid, orwith a sulfonic acid, such as a lower alkanesulfonic acid, for examplemethanesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, orwith an arylsulfonic acid, such as benzene- or naphthalene-sulfonic acidor naphthalene-1,5-di-sulfonic acid, or a double salt, such as Zn(NH₂OH)₂ Cl₂ (Crismer's reagent); or is reacted with hydroxylamine preparedin situ, for example from an alcoholic solution of nitric oxide and atin(II) salt, such as Sn(II)Cl₂, in the presence of copper salts, orfrom the potassium salt of N,O-bis trimethylsilyl!hydroxylamine(prepared from (H₃ C)₃ Si--NH--O--Si(CH₃)₃ and potassium hydride intetrahydrofuran, with subsequent freeing of the potassium salt of thecompound of formula VI with an acid, for example ammonium chloride); thereaction being carried out in water (in the presence or absence ofsurfactants), in an aqueous solvent mixture, such as a mixture of waterwith one or more alcohols, for example methanol or ethanol, di-loweralkyl sulfoxides, such as dimethyl sulfoxide, or di-lower alkyl-loweralkanoylamides, such as dimethylformamide; in organic solvents, such asalcohols, for example methanol or ethanol, di-lower alkyl sulfoxides,such as dimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, such asdimethylformamide, or in sufficiently inert nitriles, such asacetonitrile; a mixture of such organic solvents; or in liquid ammonia,preferably in an aqueous-alcoholic solution, such as methanol/water orethanol/water; at temperatures of from -78° C. to the reflux temperatureof the corresponding reaction mixture, preferably from -30° to 100° C.,especially from 5° to 90° C., for example at approximately from 75° to80° C.; under pressures of approximately from 1 to 10000 bar,preferably, where hydroxylamine salts are used, under normal pressure;in the absence of a base or preferably, where acid salts ofhydroxylamine are used, with neutralization of the acid with a base,especially with a hydroxide, such as an alkali metal hydroxide, forexample sodium or potassium hydroxide, with a carbonate or hydrogencarbonate, especially an alkali metal or alkaline earth metal carbonateor hydrogen carbonate, for example sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate orbarium carbonate, with a salt of a weak organic acid, especially analkali metal or alkaline earth metal salt of a lower alkane-carboxylicacid, for example sodium acetate or potassium acetate, with organicnitrogen bases, especially a secondary or tertiary amine, for example acyclic 5- or 6-membered secondary or tertiary amine, such as pyrrolidineor pyridine, or with alcoholates, for example alkali metal lower alkylalcoholates, such as sodium or potassium methanolate, ethanolate ortert-butanolate, or with an anion exchanger, the presence of an alkalimetal carbonate being especially preferred; the corresponding compoundof formula IV being obtained. Preferably, one of the mentioned salts ofhydroxylamine, especially the salt of a hydrohalic acid, such as thehydrochloride salt, is reacted in the mentioned organic solvents,especially in an alcohol, such as methanol or ethanol, at the mentionedtemperatures, especially at approximately from 75° to 80° C., to yieldthe corresponding oxime of formula IV, which can be purified or is usedfurther directly.

N-Hydroxyamidino compounds of formula IV (R₁ =OH) can be prepared, forexample, by reaction of an imino-(lower) alkyl ester derivative or animino-(Iower) alkanethiol ester derivative of a compound of formula VII(in salt form), wherein W₂ and W₃ together are oxo (preparation asdescribed above), or preferably directly by reaction of a compound offormula VII with hydroxylamine or with a salt thereof, compounds offormula I containing an amidino group (R₁ =H) being obtained--thereaction is carried out under conditions analogous to those describedabove for the conversion of compounds of formula VI into compounds offormula IV. Both the cyano group and the carbonyl group in the startingmaterial of formula VII are reacted.

Finally, a compound of formula IV wherein R₁ is hydrogen or hydroxy andthe other radicals are as defined can be obtained from a compound offormula VII wherein W₂ and W₃ together are oxo by first reacting thecarbonyl group with hydroxylamine, or with a salt thereof, underconditions analogous to those mentioned above for the reaction ofcompounds of formula VI to form compounds of formula VII, preferablyomitting the mentioned bases, there being obtained a compound of formulaVII wherein W₂ and W₃ together are hydroxyimino and the other radicalsare as defined above for the corresponding starting material underprocess a), and then (if desired after isolating the resulting compoundof formula VII) reacting the cyano group, under conditions analogous tothose described for the reaction of cyano compounds of formula II (W₁=cyano) under process a), with ammonia or hydroxylamine or a saltthereof, preferably in the presence of alcoholates, for example alkalimetal lower alkyl alcoholates, such as sodium or potassium methanolate,ethanolate or tert-butanolate, in the corresponding alcohols, forexample methanol, ethanol or tert-butanol, at preferred temperatures offrom 0° C. to the reflux temperature, especially from room temperatureto the reflux temperature.

Process c) - Formation of a Schiff's base by reaction of a carbonylderivative with an amino compound

In compounds of formulae V and VI, functional groups that are notintended to participate in the reaction may, if necessary, be inprotected form; protecting groups, processes for their introduction andprocesses for their removal from resulting protected compounds offormula I are analogous to those mentioned in the detailed descriptionof process a).

Reactive derivatives of compounds of formula VI are especially compoundsin which there is present instead of the carbonyl function in formula Ifunctionally modified or protected carbonyl in the form of di-loweralkoxymethylene, C₁ -C₂ alkylenedioxymethylene, di-loweralkylthiomethylene or C₁ -C₂ alkylenedithiomethylene.

The reaction between compounds of formula VI (oxo compound), or theirreactive derivatives, and compounds of formula V (aminoimidazole) takesplace under conditions that are knownper se, the aminoimidazole offormula V preferably being used in an approximately equimolar amount orin excess relative to the molar amount of the compound of formula VI,especially in an amount that is from 0.95 times to twice the molaramount--in particular, the reaction takes place under conditions thatare customary for the reaction of carbonyl compounds with nitrogenbases; preferably in the presence of acids, for example of a hydrohalicacid, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide orhydrogen iodide, especially hydrogen chloride, of sulfuric acid or ahydrogen sulfate, such as an alkali metal hydrogen sulfate, for examplesodium hydrogen sulfate, of phosphoric acid, a hydrogen phosphate or adihydrogen phosphate, for example an alkali metal hydrogen phosphate ordihydrogen phosphate, such as sodium hydrogen phosphate, disodiumhydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogenphosphate, or of an organic acid, especially a carboxylic acid, such asa lower alkanecarboxylic acid that is unsubstituted or substituted inthe lower alkyl moiety, preferably by halogen, such as fluorine,chlorine or iodine, for example acetic acid, chloroacetic acid,dichloroacetic acid or trifluoro- or trichloro-acetic acid, of lacticacid or of a sulfonic acid, such as a lower alkanesulfonic acid, forexample methanesulfonic acid, ethanesulfonic acid or ethanedisulfonicacid, or an arylsulfonic acid, such as benzene- or naphthalene-sulfonicacid or naphthalene-1,5-disulfonic acid; there being used especially astrong acid, such as sulfuric acid or, more especially, one of thementioned hydrohalic acids or methanesulfonic acid; in water (in thepresence or absence of surfactants) or an aqueous solvent mixture, suchas a mixture of water with one or more alcohols, for example methanol,ethanol or, especially, isopropanol, or also di-lower alkyl sulfoxides,such as dimethyl sulfoxide, or di-lower alkyl-lower alkanoylamides, suchas dimethylformamide, organic solvents, such as one or more alcohols,for example methanol or ethanol, di-lower alkyl sulfoxides, such asdimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, such asdimethylformamide, or in sufficiently inert nitrites, such asacetonitrile, a mixture of such organic solvents, preferably in anaqueous-alcoholic solution, such as in water/methanol, water/ethanol or,especially, water/isopropanol; preferably at temperatures of from -20°C. to the reflux temperature of the reaction mixture, especially attemperatures of from room temperature to the reflux temperature of thereaction mixture, more especially at approximately from 80° C. to thereflux temperature; the compound of formula I (where appropriate aftercustomary working up) being obtained directly in free form or,especially, in the form of a salt, preferably of the acid present in thereaction, for example in crystalline form. Special preference is givento the reaction of the oxo compound of formula VI and the aminoimidazoleof formula V with aqueous HCl in isopropanol at temperatures of from 80°C. to the reflux temperature (for example not higher than 120° C.).

The corresponding reactive derivatives can be prepared from the oxocompounds of formula VI under customary conditions for the preparationof ketals, acetals, thioketals or thioacetals.

The preparation of starting materials of formula VI from correspondingcompounds of formula VII has already been described in connection withthe preparation of starting materials for process b).

The preparation of the starting materials of formula V has already beendescribed in connection with the preparation of starting materials forprocess a).

Additional process measures

In the additional process measures, which are carried out if desired,functional groups in the starting materials that are not intended toparticipate in the reaction may be unprotected or in protected form, forexample protected by one or more of the protecting groups mentionedabove for process a). Some or all of the protecting groups may beintroduced and/or removed by one of the methods mentioned for processa).

The conversion of a compound of formula I wherein R₁ is hydroxy and theother radicals each have one of the meanings given, into a differentcompound of formula I wherein R₁ is hydrogen is effected by means ofreduction, especially by selective hydrogenation. The selectivehydrogenation takes place in the presence of a catalyst and to acid.There are used as catalyst(s) especially cobalt and, more especially,nickel, which is/are employed preferably as such or in finely dispersedform on carriers, such as argillaceous earth, pumice, aluminum oxide,silica gel or activated carbon, with Raney nickel being very especiallypreferred. There are used as acids especially the acids mentioned abovein the definition of salts, which acids are employed in at least anequimolar amount relative to the starting material of formula I inquestion or in excess, especially in the amount that isstoichiometrically necessary for salt formation with the basic centersof the compounds of formula I; there being used as solvents organicsolvents, such as alcohols that are inert under the reaction conditions.for example methanol, ethanol or isopropanol, ethers, such as diethylether, dioxane, tetrahydrofuran or anisole, esters, such as ethylacetate, or, if the acid is an organic acid that is liquid under thereaction conditions, that acid itself, for example acetic acid, mixturesof those solvents, mixtures of water-soluble organic solvents, such asthe mentioned alcohols or liquid organic acids, with water, or wateritself, of which solvents water, methanol or mixtures thereof are veryespecially preferred; the reaction temperature being from 0° C. to thereflux temperature of the reaction mixture, especially from 10° to 70°C., for example from approximately 20° C. to approximately 55° C., andthe reaction being carried out under slightly reduced pressure, normalpressure or slightly elevated pressure, preferably at from 0.5 to 10bar, especially the prevailing air pressure, with the introduction ofhydrogen, preferably until the calculated amount of hydrogen has beenabsorbed, especially until the absorption of hydrogen ceases by itselfunder the reaction conditions. Special preference is given tohydrogenation with hydrogen in the presence of Raney nickel in methanol,water or mixtures thereof, under normal pressure and at temperatures offrom 20° to 55° C.

The hydrogenation can also be carried out continuously, for example byallowing solutions of a starting material of formula I wherein R₁ ishydroxy to flow over fixed catalysts and bringing those solutions intocontact with hydrogen flowing the same way or in the opposite direction,under the above-mentioned conditions.

Salts can be converted into the free compounds in customary manner;metal salts and ammonium salts are converted, for example, by treatmentwith suitable acids or acid ion exchangers, and acid addition salts areconverted, for example, by treatment with a suitable basic agent orbasic ion exchangers.

Salts of free compounds of formula I having at least one salt-forminggroup can be prepared in a manner known per se. For example, salts ofcompounds of formula I having acidic groups can be formed, for example,by treatment with metal compounds, such as alkali metal salts ofsuitable organic carboxylic acids, for example the sodium salt of2-ethyl-hexanoic acid, with inorganic alkali metal or alkaline earthmetal compounds, such as the corresponding hydroxides, carbonates orhydrogen carbonates, such as sodium and potassium hydroxide, carbonateor hydrogen carbonate, with corresponding calcium compounds or withammonia or a suitable organic amine, there preferably being usedstoichiometric amounts or only a slight excess of the salt-formingagent. Acid addition salts of compounds of formula I are obtained incustomary manner, for example by treatment with an acid or with asuitable anion exchange reagent. Internal salts of compounds of formulaI, which contain acidic and basic salt-forming groups, for example afree carboxy group and a free amino group, can be formed, for example,by neutralization of salts, such as acid addition salts, to theisoelectric point, for example with weak bases, or by treatment with ionexchangers.

Isomeric mixtures of compounds of formula I, that is to say mixtures ofdiastereoisomers and/or enantiomers, for example racemic mixtures, canbe separated into the corresponding isomers in a manner known per se bysuitable methods of separation. For example, diastereoisomeric mixturescan be separated into the individual diastereoisomers by fractionalcrystallization, chromatography, solvent partitioning or other customarymethods. Racemates can be separated from one another after conversion ofthe optical antipodes into diastereoisomers, for example by reactionwith optically active compounds, for example with optically active acidsor bases by the formation of salts with optically pure salt-formingreagents, and separation of the diastereoisomeric mixture so obtainable,for example by means of fractional crystallization; by chromatography oncolumn materials charged with optically active compounds; or byenzymatic methods, for example by selective reaction of only one of thetwo enantiomers. The separation may be effected either at the stage ofone of the starting materials or with the compounds of formula Ithemselves.

General process conditions

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, preferably those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, preferably solvents or diluents that are inerttowards the reagents used and are solvents therefor, in the absence orpresence of catalysts, condensation agents or neutralizing agents, forexample ion exchangers, such as cation exchangers, e.g. in the H⁺ form,depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from approximately -100° C. to approximately 190° C.,preferably from approximately -80° C. to approximately 150° C., forexample at from -80° to -60° C., at from -20° to 40° C., for example atroom temperature, or at the reflux temperature, under atmosphericpressure or in a closed vessel, where appropriate under reduced orelevated pressure, in an inert atmosphere, for example under an argon ornitrogen atmosphere, and/or with the exclusion of light.

At all stages of the reactions, mixtures of isomers that are formed can,if desired, be separated into the individual isomers, for examplediastereoisomers or enantiomers, or into any desired mixtures ofisomers, for example racemates or mixtures of diastereoisomers, forexample analogously to the methods described under "Additional processmeasures".

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include, for example, water, esters,such as lower alkyl lower alkanoates, for example ethyl acetate, ethers,such as aliphatic ethers, for example diethyl ether or1,2-di-methoxyethane, or cyclic ethers, for example tetrahydrofuran,liquid aromatic hydrocarbons, such as benzene, toluene or o-, m- orp-xylene, liquid acyclic hydrocarbons, such as hexane or heptane,alcohols, such as methanol, ethanol, 1- or 2-propanol or diethyleneglycol, nitrites, such as acetonitrile, halogenated hydrocarbons, suchas methylene chloride or chloroform, acid amides, such asdimethylformamide or dimethylacetamide, ketones, such as loweralkanones, for example acetone, heterocyclic solvents, for examplebases, such as heterocyclic nitrogen bases, for example pyridine, or1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidone (DMPU), carboxylicacids, such as acetic acid or formic acid, carboxylic acid anhydrides,such as lower alkanoic acid anhydrides, for example acetic anhydride,cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane oriso-pentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvents, or mixtures thereof, may also be used inworking up, for example by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization.

Working up after reactions is carried out, if desired, in accordancewith methods known per se, preferably analogously to the methodsdescribed in the Examples.

Many of the starting materials mentioned are already known or can beprepared in accordance with processes known per se, for example asdescribed in European Patent Application EP 0 538 193 (published on 21stApr. 1993), in European Patent Application EP 0 456 133 (published on13th Nov. 1991) or in Hungarian Patent Application HU 93 02416(published on 28th Jun. 1994).

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out, orin which a starting material is formed under the reaction conditions oris used in the form of a derivative, for example in protected form or inthe form of a salt, or a compound obtainable by the process according tothe invention, or a salt thereof, is produced under the processconditions and processed further in situ. In the process of the presentinvention there are preferably used those starting materials whichresult in the compounds described at the beginning as being especiallyvaluable. Special preference is given to reaction conditions that areanalogous to those mentioned in the Examples.

If necessary or desired, protected starting materials can be used in allprocess steps and the protecting groups can be removed at suitablestages of the reaction.

Protecting groups, the introduction and the freeing thereof are asdescribed in process a).

In view of the close relationship between the compounds of formula I andtheir starting materials in free form and in the form of salts, anyreference hereinbefore and hereinafter to the free compounds andstarting materials or their salts is to be understood as meaning alsothe corresponding salts or free compounds and starting materials,respectively, where appropriate and expedient.

Pharmaceutical processes and compositions

The present invention relates also to pharmaceutical compositions thatcomprise one of the pharmacologically active compounds of formula I asactive ingredient. Compositions for enteral, especially oral, andparenteral administration are especially preferred. The compositionscomprise the active ingredient on its own or, preferably, together witha pharmaceutically acceptable carrier. The dose of active ingredientdepends upon the disease to be treated, the species, age, weight andindividual condition of the individual to be treated, and the mode ofadministration.

The pharmaceutical compositions comprise from approximately 0.1% toapproximately 95% active ingredient, dosage forms that are in singledose form preferably comprising from approximately 1% to approximately90% active ingredient, and dosage forms that are not in single dose formpreferably comprising from approximately 0.1% to approximately 20%active ingredient. Unit dose forms, such as dragees, tablets orcapsules, comprise from approximately 1 mg to approximately 500 mg ofactive ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilizing processes. Forexample, pharmaceutical compositions for oral administration can beobtained by combining the active ingredient with one or more solidcarriers, optionally granulating a resulting mixture, and, if desired,processing the mixture or granules, if appropriate by the addition ofadditional excipients, to form tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tri-calcium phosphate or calciumhydrogen phosphate, and also binders, such as starches, for examplecorn, wheat, rice or potato starch, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabove-mentioned starches and also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, or alginic acid or a salt thereof, such as sodiumalginate.

Additional excipients are especially flow conditioners and lubricants,for example silicic acid, talc, stearic acid or salts thereof, such asmagnesium or calcium stearate, and/or polyethylene glycol, orderivatives thereof.

Dragee cores can be provided with suitable, optionally enteric,coatings, there being used inter alia concentrated sugar solutions,which may comprise gum arabic, talc, polyvinyl-pyrrolidone, polyethyleneglycol and/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Colorings or pigments may be added to the tablets or dragee coatings,for example for identification purposes or to indicate different dosesof active ingredient.

Pharmaceutical compositions for oral administration are also hardgelatin capsules, and soft sealed capsules consisting of gelatin and aplasticizer, such as glycerol or sorbitol. The hard gelatin capsules maycontain the active ingredient in the form of granules, for example inadmixture with fillers, such as corn starch, binders and/or glidants,such as talc or magnesium stearate, and, where appropriate, stabilizers.In soft capsules the active ingredient is preferably dissolved orsuspended in suitable liquid excipients, for example fatty oils,paraffin oil or liquid polyethylene glycols, it likewise being possibleto add stabilizers.

Other oral dosage forms are, for example, syrups prepared in customarymanner which comprise the active ingredient, for example, in dispersedform and in a concentration of approximately from 0.1% to 10%,preferably approximately 1% or in a similar concentration that providesa suitable single dose when administered, for example, in a measure of 5or 10 ml. Also suitable are, for example, powdered or liquidconcentrates for the preparation of shakes, for example in milk. Suchconcentrates may also be packaged in single dose quantities

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient with a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols.

For parenteral administration there are suitable, especially, aqueoussolutions (preferably in the presence of sodium chloride) of an activeingredient in water-soluble form, for example in the form of awater-soluble salt, or aqueous injection suspensions that compriseviscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilizers. The active ingredient, where appropriate together withexcipients, can also be in the form of a lyophilisate and be made into asolution prior to parenteral administration by the addition of suitablesolvents.

Solutions of the kind used, for example, for parenteral administrationcan also be used as infusion solutions.

The invention relates also to pharmaceutical compositions and to amethod for the (therapeutic or prophylactic) treatment of theabove-mentioned diseases, for example of tumors, metastases or protozoaldiseases, an amount of a compound of formula I according to theinvention that is prophylactically, or preferably, therapeuticallyeffective against the mentioned diseases being present in apharmaceutical composition that is suitable for administration to awarm-blooded animal, especially a human, requiring that treatment forthe treatment of one of the mentioned diseases; and a therapeuticallyeffective amount of a compound of formula I according to the inventionbeing administered in the treatment method to a warm-blooded animal, forexample a human, requiring such treatment on account of one of thementioned diseases, in an amount that is prophylactically ortherapeutically effective against that disease.

The invention relates also to a method of treating the above-mentionedpathological conditions.

Accordingly, the compounds of the present invention can be administeredprophylactically or therapeutically, preferably in the form ofpharmaceutical compositions. For a body weight of approximately 70 kg, adaily dose of from approximately 1 mg to approximately 1000 mg,preferably of approximately from 25 to 100 mg orally. and from 2 to 50mg parenterally, of a compound of the present invention is administered.Children usually receive half the adult dose.

The following Examples serve to illustrate the invention, but do notlimit the scope thereof in any way.

Temperatures are given in degrees Celsius.

The following abbreviations are used: DMF=N,N-dimethylformamide;DMSO=dimethyl sulfoxide; MS (FAB)=mass spectrum (fast atom bombardment).

N-Hydroxyamidino is the group --C(═NOH)--NH₂.4-Tolyl is thep-methylphenyl radical.

EXAMPLE 1

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazoledihydrochloride

6 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) areadded, with stirring, to a mixture of 4.1 g (0.02 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 3.5 g (0.02 mol)of 1,2-diamino-4-phenyl-imidazole (see Beyer H. et al., Chem. Ber. 101,3151 (1968)) and 150 ml of isopropanol, and the mixture is stirred at80° C. for 5 hours. During that time, the starting materials dissolveand the title compound gradually crystallizes out. At the end of thereaction time, the mixture is cooled. The product that has crystallizedout is filtered off with suction, washed with isopropanol and dried. Theproduct crystallizes with one mole of isopropanol, m.p. 238°-240° C., ¹H-NMR (DMSO/D₂ O): δ=8.24 (d, 1H); 7.88 (s, 1H); 7.73 (d, 1H); 7.55-7.68(m, 3H); 7.34-7.5 (m, 3H); 3.26 (s, 4H).

(For another method of synthesis, see Example 32).

The starting material is prepared as follows:

a) 4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime

Variant 1:

A mixture of 20.43 g (0.13 mol) of 4-cyano-2,3-dihydro-1H-inden-1-oneColl. Czechoslov. Chem. Commun. 43, 3227 (1978)!, 18.07 g (0.26 mol) ofhydroxylamine hydrochloride, 13.46 g (0.127 mol) of sodium carbonate and650 ml of 50% aqueous ethanol is stirred at 800 for 3.5 h6urs. A further9.035 g (0.13 mol) of hydroxylamine hydrochloride and 6.73 g (0.0635mol) of sodium carbonate are then added to the reaction mixture,stirring is continued at 80° for a further 5 hours, and the reactionmixture is allowed to cool slowly to room temperature. The reactionmixture is then cooled to 10° and is filtered, and the resulting productis washed with 20 ml of 50% aqueous ethanol and a small amount ofdiethyl ether. The crystallizate is then added to 900 ml of methanol,the mixture is stirred at room temperature for one hour, insolubleconstituents are filtered off, and the filtrate is concentrated to avolume of approximately 150 ml. The product precipitated on cooling to5° C. is filtered off, washed with a small amount of methanol anddiethyl ether, and dried. The title compound so obtained melts at192°-194° (decomp.).

Variant 2:

10.4 g (150 mmol) of hydroxylamine hydrochloride and 37.5 ml of 2M Na₂CO₃ solution are added, with stirring, to a solution of 7.86 g (50 mmol)of 4-cyano-2,3-dihydro-1H-inden-1-one Coll. Czechoslov. Chem. Commun. 433227 (1978)! in 75 ml of N,N-dimethylformamide, and the reaction mixtureis heated at 75° C. for 3.75 hours. While still warm, the reactionmixture is diluted with 25 ml of water and is filtered while warm. 88 mlof water are then added to the filtrate, with stirring, and the mixtureis cooled to 0°-5° C. The product that has crystallized out is filteredoff with suction, is washed with DMF/water 1:3 and finally with ethanol,is dried and is recrystallized from three times the amount of DMF. Inthat manner there is obtained the title compound, which melts at192°-194° (decomp.); MS (FAB): (M+H)⁺ =206; ¹ H-NMR (DMSO): δ=10.87 (s,1H); 9.64 (s, 1H); 7.56 (d, 1H); 7.49 (d, 1H); 7.30 (t, 1H); 5.76 (s,2H); 3.15 (t, 2H); 2.74 (t, 2H).

Variant 3:

A mixture of 157 mg (1.0 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-oneColl. Czechoslov. Chem. Commun. 43, 3227 (1978)! and 139 mg (2.0 mmol)of hydroxylamine hydrochloride in 4 ml of ethanol is stirred at 80° C.for 1.5 hours and cooled in an ice-water bath. The product that hascrystallized out is filtered off with suction, washed with cold ethanoland diethyl ether and dried. In that manner there is obtained theintermediate 4-cyano-2,3-dihydro-1H-inden-1-one oxime, which melts at200°-202° C. with decomposition; ¹ H-NMR (DMSO): δ=11.22 (s, 1H); 7.84(d, 1H); 7.81 (d, 1H); 7.45 (t, 1H); 3.15 (t, 2H); 2.84 (t, 2H).

920 mg (5.1 mmol) of sodium methanolate are added to a mixture of 360 mg(2.06 mmol) of the intermediate 4-cyano-2,3-dihydro-1H-inden-1-one oximeand 355 mg (5.1 mmol) of hydroxylamine hydrochloride in 10 ml ofmethanol, and the reaction mixture is stirred at room temperature for 10minutes. The reaction mixture is then filtered and the filtrate isboiled under reflux conditions for 2 hours. After cooling, the resultingproduct is filtered off, washed with a small amount of methanol anddried. In that manner there is obtained the title compound, which meltsat 192°-194° (decomp.); ¹ H-NMR (DMSO): δ=10.87 (s, 1H); 9.64 (s, 1H);7.56 (d, iH); 7.49 (d, 1H); 7.30 (t, 1H); 5.76 (s, 2H); 3.15 (t, 2H);2.74 (t, 2H).

EXAMPLE 2:

1- 4-(Amidino)-2,3-dihydro-1H-inden-1:-ylideneamino!-2-amino-4-phenyl-imidazole dihydrochloride

0.2 g of Raney nickel is added to a solution of 2.0 g (0.0048 mol) of 1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazoledihydrochloride in 100 ml of methanol, and hydrogenation is carried outat room temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then filtered and thecatalyst is washed thoroughly with methanol. The filtrate is adjusted topH 4 with a small amount of 2N alcoholic hydrochloric acid and isconcentrated. The product that has crystallized out is filtered off withsuction and recrystallized from 30 ml of methanol, yielding the titlecompound in the form of the trihydrate, m.p. 211°-215° C., ¹ H-NMR(DMSO): δ=9.56 (d, 4H); 8.34 (d, 1H); 8.14 (s, 1H); 7.97 (s, 2H); 7.82(m, 3H); 7.67 (t, 1H); 7.3-7.52 (m, 4H); 3.41 (s, 4H).

EXAMPLE 3

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxvphenyl)-imidazoledihydrochloride

7.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) areadded, with stirring, to a mixture of 4.92 g (0.024 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.9 g (0.024 mol)of 1,2-diamino-4-(4-methoxyphenyl)-imidazole (see Hetzheim A. et al.,Chem. Ber. 100, 3418 (1967)) and 120 ml of isopropanol, and the reactionmixture is stirred at 80° C. for 19 hours. The reaction mixture isfiltered while hot and the filtrate is cooled. The pale-yellow titleproduct that has crystallised out is filtered off with suction anddried. It crystallizes in the form of the monohydrate, m.p. >220° C., MS(FAB): (M+H)⁺ =377, ¹ H-NMR (DMSO/D₂ O): δ=8.23 (d, 1H); 7.74 (s, 1H);7.72 (d, 1H); 7.57-7.63 (m, 3H); 7.02 (d, 2H); 3.75 (s, 3H), 3.26 (s,4H).

EXAMPLE 4

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxvphenyl)-imidazoledihydrochloride

Analogously to Example 2, approximately 2 g of Raney nickel are added toa solution of 5.8 g (0.00129 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxyphenyl)-imidazoledihydrochloride in 600 ml of methanol, and hydrogenation is carried outat room temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then filtered and thefiltrate is concentrated. The product that has crystallised out isfiltered off with suction and recrystallized from methanol, yielding thetitle compound in the form of the monohydrate, m.p. >220° C., ¹ H-NMR(DMSO): δ=9.56 (d, 4H); 8.33 (d, 1H); 7.99 (s, 1H); 7.94 (s, 2H);7.75-7.84 (m, 3H); 7.64 (t, 1H); 7.04 (d, 2H); 3.80 (s, 3H), 3.40 (m,4H).

EXAMPLE 5

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-l1-ylideneamino!-2-amino-4-(2-methoxyphenyl)-imidazoledihydrochloride

0.6 ml of 32 % hydrochloric acid (Merck, Darmstadt, Germany; p.a.) isadded, with stirring, to a mixture of 0.41 g (0.002 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.408 g (0.002mol) of 1,2-diamino-4-(2-methoxyphenyl)-imidazole and 10 ml ofisopropanol, and the reaction mixture is stirred at 80° C. for 20 hours.The reaction mixture is filtered while hot and the filtration product iswashed with isopropanol and dried. In that manner there is obtained thetitle compound, m.p. >220° C., ¹ H-NMR (DMSO/D₂ O): δ=8.22 (d, 1H); 7.77(m, 2H); 7.58 (m, 2H); 7.36 (m, 1H); 7.12 (d, 1H); 7.05 (t, 1H); 3.88(s, 3H), 3.24 (s, 4H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole

A solution of 41.7 g (0.257 mol) of benzaldehyde guanylhydrazone (seeThiele, A., Liebigs Annalen der Chemie 270, 35) and 30.12 g of2-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98%, Cat. no.10,085-4) in 130 ml of ethanol is boiled under reflux for one hour.After cooling, the product that has crystallised out is filtered offwith suction and recrystallized from ethanol. In that manner there isobtained the title compound, m.p. 166°-167° C., ¹ H-NMR (DMSO): δ=8.61(s, 1H); 8.0 (m, 3H); 7.88 (s, 1H); 7.5 (m, 3H); 7.19 (m, 1H); 7.03 (d,1H); 6.96 (t, 1H); 6.16 (s, 2H); 3.94 (s, 3H).

b) 1,2-Diamino-4-(2-methoxyphenyl)-imidazole

A solution of 23.2 g of2-amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole and 15.8 ml ofhydrazine hydrate in 80 ml of diethylene glycol is stirred at 170° C.for 7 hours. After cooling, 400 ml of water are added to the reactionmixture. The product that has separated out is filtered off withsuction, washed with water and recrystallized from 200 ml of ethanol. Inthat manner there is obtained the title compound, m.p. 195°-196° C., ¹H-NMR (DMSO): δ=7.9 (d, 1H); 7.06 (m, 2H); 6.91 (m, 2H); 5.52 (s, 2H);5.3 (s, 2H); 3.88 (s, 3H).

EXAMPLE 6

1-4-(Armidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-methoxyphenyl)-imidazoledihydrochloride

Analogously to Example 2, approximately 0.2 g of Raney nickel is addedto a solution of 0.45 g (0.001 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-methoxyphenyl)-imidazoledihydrochloride in 50 ml of methanol/water 1:1, and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is then dilutedwith 100 ml of methanol and filtered. The filtrate is adjusted to pH 4with a small amount of 2N alcoholic hydrochloric acid and isconcentrated to dryness by evaporation. The residue is recrystallizedfrom ethyl acetate, yielding the title compound in the form of thedihydrate, m.p. >220° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.28 (d, 1H);7.80 (m, 2H); 7.64 (m, 2H); 7.38 (t, 1H); 7.16 (d, 1H); 7.06 (t, 1H);3.91 (s, 3H), 3.30 (m, 4H).

EXAMPLE 7

1- 4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-dimethoxyphenyl)-imidazole dihydrochloride

0.6 ml of concentrated hydrochloric acid is added, with stirring, to amixture of 0.41 g (0.002 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.47 g (0.002mol) of 1,2-diamino-4-(2,5-dimethoxyphenyl)-imidazole and 10 ml ofisopropanol, and the reaction mixture is stirred at 80° C. for 3.hours.The reaction mixture is filtered while hot and the filtration product iswashed with isopropanol and dried. In that manner there is obtained thetitle compound, m.p. >220° C., ¹ H-NMR (DMSO/D₂ 0): δ=8.23 (d, 1H); 7.75(m, 2H); 7.61 (t, 1H); 7.17 (d, 1H); 7.07 (d, 1H); 6.93 (q, 1H); 3.82(s, 3H), 3.71 (s, 3H); 3.25 (bs, 4H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-(2,5-dimethoxyphenyl)-imidazole

A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 1.34g of 2,5-dimethoxyphenacyl bromide (Aldrich, Buchs, Switzerland, 97%,Cat. no. 10,458-2) in 5 ml of ethanol is boiled under reflux for 45minutes. After cooling, the product that has crystallized out isfiltered off with suction and recrystallized from ethanol. In thatmanner there is obtained the title compound, m.p. 180°-181° C., ¹ H-NMR(DMSO): δ=8.62 (s, 1H); 7.97 (m, 2H); 7.90 (s, 1H); 7.42-7.60 (m, 4H);6.95 (d, 1H); 6.76 (m, 1H); 6.18 (s, 2H); 3.9 (s, 3H); 3.73 (s, 3H).

b) 1.2-Diamino-4-(2,5-dimethoxyphenyl)-imidazole

A solution of 26.1 g of2-amino-1-benzylideneamino-4-(2,5-dimethoxyphenyl)-imidazole and 16.2 mlof hydrazine hydrate in 80 ml of diethylene glycol is stirred at 170° C.for 6 hours. After cooling, 400 ml of water are added to the reactionmixture. The product that has separated out is filtered off withsuction, washed with water and recrystallized from 150 ml of ethanol. Inthat manner there is obtained the title compound, m.p. 159°-160° C., ¹H-NMR (DMSO): δ=7.47 (d, 1H); 7.07 (s, 1H); 6.87 (d, 1H); 6.63 (q, 1H);5.52 (s, 2H); 5.34 (s, 2H); 3.79 (s, 3H); 3.69 (s, 3H).

EXAMPLE 8

1-4-(Amidino)-213-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-di-methoxyphenyl)-imidazoledihydrochloride

Analogously to Example 2, approximately 0.2 g of Raney nickel is addedto a solution of 0.48 g (0.001 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-dimethoxyphenyl)-imidazoledihydrochloride in 50 ml of methanol/water 1:1, and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is then dilutedwith 100 ml of methanol and filtered. The filtrate is adjusted to pH 4with a small amount of 2N alcoholic hydrochloric acid and isconcentrated in vacuo to approximately 50 ml. The product that hascrystallized out, which is filtered off with suction and dried, is thetitle compound in the form of the dihydrate, m.p. 260° C. (decomp.), ¹H-NMR (DMSO/D₂ O): δ=8.27 (d, 1H); 7.82 (m, 2H); 7.64 (t, 1H); 7.28 (d,1H); 7.09 (d, 1H); 6.94 (q, 1H); 3.76 (s, 3H), 3.30 (m, 4H).

EXAMPLE 9

1- 4-(N-Hydroxvamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazole dihydrochloride

6.0 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) areadded, with stirring, to a mixture of 4.1 g (0.02 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.08 g (0.02 mol)of 1,2-diamino-4-(3-methoxyphenyl)-imidazole and 100 ml of isopropanol,and the reaction mixture is stirred at 80° C. for 18 hours. The reactionmixture is filtered while hot and the filtration product is washed withisopropanol and dried. In that manner there is obtained the titlecompound, m.p. 257°-259° C., ¹ H-NMR (DMSO/D₂ O): δ=8.24 (d, 1H); 7.91(s, 1H); 7.75 (d, 1H); 7.61 (t, 1H); 7.38 (t, 1H); 7.25 (m, 2H); 6.95(m, 1H); 3.76 (s, 3H), 3.27 (s, 4H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole

A solution of 16.2 g (0.1 mol) of benzaldehyde guanylhydrazone and 11.8g (0.050 mol) of 3-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland;98 %, Cat. no. 11,567-3) in 50 ml of ethanol is stirred at 20° C. for 3hours. The product that has crystallized out is filtered off withsuction and dried. In that manner there is obtained the title compound,m.p. 170°-171° C., ¹ H-NMR (DMSO): δ=8.56 (s, 1H); 8.03 (s, 1H); 7.92(m, 2H); 7.5 (m, 3H); 7.26 (m, 3H); 6.76 (m, 1H); 6.2 (s, 2H); 3.8 (s,3H).

b) 1,2-Diamino-4-(3-methoxy-phenyl)-imidazole

A solution of 8.1 g of2-amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole and 5.5 ml ofhydrazine hydrate in 28 ml of diethylene glycol is stirred at 170° C.for 7 hours. After cooling, 150 ml of water are added to the reactionmixture. The product that has separated out is filtered off withsuction, washed with water and recrystallized from 100 ml of ethanol. Inthat manner there is obtained the title compound, m.p. 181°-182° C., ¹H-NMR (DMSO): δ=7.17 (m, 3H); 7.06 (s, 1H); 6.64 (m, 1H); 5.52 (s, 2H);5.35 (s, 2H); 3.74 (s, 3H).

EXAMPLE 10

1- 4-(Amidino)-2,3-dihydro-1 1H-inden-1-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazole dihydrochloride

Analogously to Example 2, approximately 2 g of Raney nickel are added toa solution of 4.1 g (0.008 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazoledihydrochloride in 410 ml of water, and hydrogenation is carried out atroom temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then diluted with 1.3liters of methanol and filtered. The filtrate is adjusted to pH 4 with asmall amount of 2N alcoholic hydrochloric acid and is concentrated invacuo to approximately 200 ml. The product that has crystallized out,which is filtered off with suction and dried, is the title compound inthe form of the monohydrate, m.p. 260° C. (decomp.), ¹ H-NMR (DMSO/D₂O): δ=8.32 (d, 1H); 8.05 (s, 1H); 7.83 (d, 1H); 7.65 (t, 1H); 7.3-7.44(m, 3H); 6.94 (d, 1H); 3.81 (s, 3H); 3.36 (s, 4H).

EXAMPLE 11

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-chlorophenyl)-imidazoledihydrochloride

A mixture of 1.026 g (5 mmol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.043 g (5 mmol)of 1,2-diamino-4-(4-chlorophenyl)-imidazole (see Beyer H. et al., Chem.Ber. 101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at120° C. for 18 hours, with stirring, and is then concentrated byevaporation in vacuo. 25 ml of ethanol are added to the crystallineresidue, the mixture is cooled to 5° C., with stirring, and is filtered,and the crystallizate is washed with a small amount of ethanol anddiethyl ether. The crude title compound, dried under a high vacuum,contains 8.17% water and melts at 226°-228° C. (decomp.), ¹ H-NMR (D₂O): δ=8.06 (d, 1H); 7.75 (d, 1H); 7.55 (t, 1H); 7.40 (s, 1H); 7.38 (d,2H); 7.28 (d, 2H); 3.21-3.27 (m, 2H), 3.03-3.09 (m, 2H).

EXAMPLE 12

1- 4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-chlorophenyl)-imidazole dihydrochloride

Analogously to Example 2, 0.2 g of Raney nickel is added to a solutionof 1.0 g (2.024 mmol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-chlorophenyl)-irnidazoledihydrochloride in 35 ml of methanol and 20 ml of water, andhydrogenation is carried out at room temperature and under normalpressure until the absorption of hydrogen has ceased. The reactionmixture is then diluted with 50 ml of methanol and filtered. Thefiltrate is adjusted to pH 3 with a small amount of 3N methanolichydrochloric acid and is concentrated to a volume of approximately 30ml. After cooling in an ice-bath, the product that has crystallized outis filtered off, washed with a small amount of methanol and diethylether and dried under a high vacuum at 120° C. The title compound isobtained in the form of the monohydrate, m.p. 245°-250° C. (decomp.), ¹H-NMR (DMSO/D₂ O): δ=8.33 (d, 1H); 8.12 (s, 1H); 7.79-7.87 (m, 3H); 7.67(t, 1H); 7.57 (d, 2H); 3.38 (s, 4H).

EXAMPLE 13

1-4-(N-Hydroxyamidino)-2.3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tolyl)-imidazoledihydrochloride

A mixture of 1.20 g (5.848 mmol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.10 g (5.844mmol) of 1,2-diamino-4-(4-tolyl)-imidazole (Beyer H. et al., Chem. Ber.101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 110° C.for 22 hours, with stirring, and is then concentrated in vacuo toapproximately half its original volume. The product that hascrystallized out is filtered off, washed with isopropanol andrecrystallized from a mixture of 15 ml of methanol and 30 ml ofisopropanol, yielding the title compound in the form of the dihydrate,m.p. 225°-232° C. (decomp.), ¹ H-NMR (D₂ O): δ=8.04 (d, 1H); 7.74 (d,1H); 7.55 (t, 1H); 7.30 (s, 1H); 7.26 (d, 2H); 7.07 (d, 2H); 3.17-3.23(m, 2H); 2.98-3.04 (m, 2H); 2.07 (s, 3H).

EXAMPLE 14

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tolyl)-imidazoledihydrochloride

Analogously to Example 2, 0.2 g of Raney nickel is added to a solutionof 0.9 g (1.917 mmol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tolyl)-imidazoledihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is thenfiltered, and the filtrate is acidified to pH 3 with 3N methanolichydrochloric acid and is concentrated to a volume of approximately 20ml. The product that has crystallized out is filtered off andrecrystallized from ethanol/water, yielding the title compound with awater content of 11.81%, m.p. 220°-225° C. (decomp.), ¹ H-NMR (DMSO/D₂O): δ=8.33 (d, 1H); 7.98 (s, 1H); 7.83 (d, 1H); 7.61-7.71 (m, 3H); 7.29(d, 2H); 3.37 (s, 4H); 2.34 (s, 3H).

EXAMPLE 15

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluorophenyl)-imidazoledihydrochloride

1.91 ml of 37% hydrochloric acid are added, with stirring, to a mixtureof 1.303 g (6.35 mmol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.22 g (6.348mmol) of 1,2-diamino-4.-(4-fluorophenyl)-imidazole and 32 ml ofisopropanol, and the reaction mixture is stirred at 110° C. for 4 hours.Filtration of the hot reaction mixture, washing of the crystallizatewith isopropanol and drying under a high vacuum yield the title compoundin the form of the monohydrate with an isopropanol content of 4.17%,m.p. 242°-247° C. (decomp.), ¹ H-NMR (D₂ O): δ=8.12 (d, 1H); 7.79 (d,1H); 7.52-7.63 (m, 3H); 7.47 (s, 1H); 7.65 (t, 2H); 3.28-3.32 (m, 2H);3.16-3.20 (m, 2H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-(4-fluorophenyl)-imnidazole

7.32 ml (0.0525 mol) of triethyl amine and 8.63 g (0.05 mol) of2-chloro-4'-fluoro-aceto-phenone (Aldrich, Buchs, Swilzerland; 99%, Cat.no. 13,288-8) are added to a solution of 8.11 g (0.05 mol) ofbenzaldehyde guanylhydrazone in 40 ml of ethanol. The reaction mixtureis stirred at 20° C. for 0.5 hour and is then boiled under reflux for2.5 hours. After cooling to 5° C., the product that has crystallized outis filtered off, washed with diethyl ether and dried. In that mannerthere is obtained the title compound, m.p. 207°-210° C., ¹ H-NMR (DMSO):δ=8.55 (s, 1H); 8.00 (s, 1H); 7.90-7.98 (m, 2H); 7.69-7.79 (m, 2H);7.45-7.57 (m, 3H); 7.15-7.27 (m, 2H); 6.22 (s, 2H).

b) 1,2-Diamino-4-(4-fluorophenyl)-imidazole

A solution of 5.3 g (0.0189 mol) of2-amino-1-benzylideneamino-4-(4-fluorophenyl)-imidazole and 12.5 ml ofhydrazine hydrate in 18.8 ml of diethylene glycol is stirred at 140° C.for 15 hours. After cooling to 80° C., 70 ml of acetonitrile are addedto the reaction mixture, which is then cooled further to 0° C. Theproduct that has separated out is filtered off and washed withacetonitrile and diethyl ether. In that manner there is obtained thetitle compound, m.p. 227°-230° C., ¹ H-NMR (DMSO): δ=7.57-7.68 (m, 2H);7.06-7.15 (m, 2H); 7.01 (s, 1H); 5.52 (s, 2H); 5.36 (s, 2H).

EXAMPLE 16

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluoro-phenyl)-imidazoledihydrochloride

Analogously to Example 2, 0.25 g of Raney nickel is added to a solutionof 1.0 g (2.105 mmol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluorophenyl)-imidazoledihydrochloride in 70 ml of methanol/water (1:1), and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is thenfiltered, the filtrate is acidified to pH 3 with 3N methanolichydrochloric acid, and concentration is carried out by evaporation invacuo. The crystalline residue is recrystallized from methanol/diethylether, yielding the title compound with a water content of 4.88%, m.p.245°-250° C. (decomp.), ¹ H-NMR (D₂ O): δ=8.09 (d, 1H); 7.81 (d, 1H);7.44-7.61 (m, 3H); 7.42 (s, 1H); 7.03-7.15 (m, 2H); 3.27-3.33 (m, 2H);3.11-3.17 (m, 2H).

EXAMPLE 17

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazoledihydrochloride

3.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) areadded, with stirring, to a mixture of 3.28 g (0.016 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 2.6 g (0.016 mol)of 1,2-diamino-4-ethyl-imidazole hydrochloride and 150 ml ofisopropanol, and the reaction mixture is stirred at 80° C. for 90 hours.The reaction mixture is filtered while hot and the filtration product iswashed with isopropanol and dried. In that manner there is obtained thetitle compound, m.p. 245°-246° C., ¹ H-NMR (DMSO/D₂ O): δ=8.22 (d, 1H);7.73 (d, 1H); 7.59 (t, 1H); 7.19 (s, 1H); 3.2 (m, 4H); 2.47 (m, 2H);1.17 (t, 3H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-ethyl-imidazole

A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 0.84g (0.005 mol) of 1-bromo-2-butanone (Aldrich, Buchs, Switzerland; tech.90%, Cat. no. 24,329-9) in 5 ml of ethanol is stirred for one hour in anice-water bath and for 16 hours at 20° C. The reaction mixture is thenconcentrated to dryness by evaporation. The residue is taken up inlethyl acetate, washed twice with water and once with dilute sodiumchloride solution, and dried over MgSO₄. The ethyl acetate solution isconcentrated, whereupon the title compound crystallizes out, m.p.164°-167° C., ¹ H-NMR (DMSO): δ=8.41 (s, 1H); 8.89 (m, 2H); 7.46 (m,3H); 7.13 (s, 1H); 5.9 (s, 2H); 2.34 (q, 2H); 1.13 (t, 3H).

b) 1,2-Diamino-4-ethyl-imidazole hydrochloride

A mixture of 4.29 g (0.02 mol) of2-amino-1-benzylideneamino-4-ethyl-imidazole and 25 ml of 2Nhydrochloric acid is heated to 120° C. and subjected to steamdistillation for one hour. The distillation residue is cooled and thenconcentrated to dryness by evaporation, and the residue is crystallizedfrom ethanol/ethyl acetate. In that manner there is obtained the titlecompound, m.p. 124°-125° C., ¹ H-NMR (DMSO/D₂ 0) δ=6.53 (s, 1H); 2.36(q, 2H); 1.07 (t, 3H).

EXAMPLE 18

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazoledihydrochloride

Analogously to Example 2, approximately 0.4 g of Raney nickel is addedto a solution of 1.0 g (0.0027 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-l1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazoledihydrochloride in 100 ml of methanol, and hydrogenation is carried outat room temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then filtered, adjusted topH 4 with a small amount of 2N alcoholic hydrochloric acid andconcentrated to dryness by evaporation. The residue is recrystallizedfrom ethanol, yielding the title compound in the form of the dihydrate,m.p. >240° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.21 (d, 1H); 7.75 (d,1H); 7.6 (t, 1H); 7.18 (s, 1H); 3.26 (m, 2H); 3.18 (m, 2H); 2.46 (q.2H): 1.15 (t, 3H).

EXAMPLE 19

1- 4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazole dihydrochloride

0.5 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) isadded, with stirring, to a mixture of 0.51 g (0.0025 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.342 g (0.0025mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride m.p. 245°-246°C.; prepared from the corresponding p-toluenesulfonate salt, see EP 0327 919, Example 12, by ion exchange on ®Amberlite IRA-400 (anionexchanger based on a styrene/divinylbenzene polymer with quaternaryammonium groups in the Cl⁻ form; Fluka, Buchs, Switzerland)! and 12 mlof isopropanol, and the reaction mixture is stirred at 80°-90° C. for 16hours. The reaction mixture is filtered while hot and the filtrationproduct is washed with isopropanol and recrystallized from hot water. Inthat manner there is obtained the title compound, m.p. >245° C., ¹ H-NMR(D₂ O): δ=8.08 (d, 1H); 7.72 (d, 1H); 7.56 (t, 1H); 4.14 (t, 2H); 3.81(t, 2H); 3.3 (m, 2H); 3.15 (m, 2H).

EXAMPLE 20

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-di-hydro-imidazoledihydrochloride

Analogously to Example 2, approximately 2.0 g of Raney nickel are addedto a solution of 4.75 g (0.0138 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazoledihydrochloride in 240 ml of water, and hydrogenation is carried out atroom temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then filtered, adjusted topH 4 with a small amount of 2N alcoholic hydrochloric acid andconcentrated to dryness by evaporation. The residue is recrystallizedfrom water, yielding the title compound in the form of the monohydrate,m.p. 280° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.17 (d, 1H); 7.66 (d,1H); 7.54 (t, 1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m,2H).

EXAMPLE 21

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-biphenylyl)-imidazoledihydrochloride

20 ml of concentrated hydrochloric acid are added, with stirring, to amixture of 5.09 g (0.0248 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 6.23 g (0.0248mol) of 1,2-diamino-4-(4-biphenylyl)-imidazole and 70 ml of isopropanol,and the mixture is stirred at 120° C. for 28 hours. Cooling to roomtemperature, filtration, washing the crystallizate with isopropanol anddrying under a high vacuum yield the title compound with a water contentof 0.9%, m.p. 284°-285° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.28 (d,1H); 7.99 (s, 4H); 7.80 (s, 4H); 7.60-7.76 (m, 4H); 7.35-7.53 (m, 3H);3.32 (s, 4H).

The starting materials are prepared as follows:

a) 2-Amino-1-benzylideneamino-4-(4-biphenylyl)-imidazole

7 ml (0.0507 mol) of triethylamine and 13.75 g (0.050 mol) of2-bromo-4'-phenylaceto-phenone (Aldrich, Buchs, Switzerland; tech., Cat.no. 10,108-7) are added to a solution of 8.11 g (0.05 mol) ofbenzaldehyde guanylhydrazone in 40 ml of ethanol. The reaction mixtureis stirred at 20° C. for 15 hours and is filtered, and the crystallizateis taken up in methylene chloride and acidified to pH 1 with 1Nhydrochloric acid. After filtration, the filtration product is taken upin methanol, and 2N sodium hydroxide solution is added until a basicreaction is obtained (pH 11). Filtration is carried out and thecrystalline product is washed with methanol/water (1:1). The titlecompound so obtained melts at 254°-255° C. (decomp.), ¹ H-NMR (DMSO):δ=8.60 (s, 1H); 8.10 (s, 1H); 7.93-7.98 (m, 2H); 7.67-7.83 (m, 6H);7.32-7.55 (m, 6H); 6.24 (s, 2H).

b) 1,2-Diamino-4-(4-biphenylyl)-imidazole

A solution of 9.2 g (0.0189 mol) of2-amino-1-benzylideneamino-4-(4-biphenylyl)-imidazole and 22 ml ofhydrazine hydrate in 73 ml of diethylene glycol is stirred at 140° C.for 48 hours. After cooling to 20° C., 100 ml of acetonitrile are addedto the reaction mixture, which is then cooled further to 5° C. Theproduct that has separated out is filtered off and washed withacetonitrile and diethyl ether. In that manner there is obtained thetitle compound having a water content of 0.41 %, m.p. >280° C., ¹ H-NMR(DMSO): δ=7.29-7.73 (m, 9H); 7.12 (s, 1H); 5.55 (s, 2H); 5.39 (s, 2H).

EXAMPLE 22

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-bi-phenylyl)-imidazoledihydrochloride

Analogously to Example 2, a mixture of 9.27 g (18.54 mmol) of 1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-biphenylyl)-imidazoledihydrochloride, 800 ml of water, 820 ml of methanol and 7.3 g of Raneynickel is hydrogenated at 25°-51° C. and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is thenfiltered, the filtrate is acidified to pH 1 with concentratedhydrochloric acid, and concentration is carried out by evaporation invacuo. Recrystallization of the residue twice from ethanol yields thetitle compound, m.p. 269°-270° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.32(d, 1H); 8.03 (s, 1H); 7.62-7.83 (m, 8H); 7.35-7.53 (m, 3H); 3.36 (s,4H).

EXAMPLE 23

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)-imidazoledihydrochloride

7 ml of concentrated hydrochloric acid are added, with stirring, to amixture of 2.01 g (9.8 mmol) of4-(N-hydroxyarnidino)-2,3-dihydro-1H-inden-1-one oxime, 2.2 g (9.8 mmol)of 1,2-diamino-4-(2-naphthyl)-imidazole (see J. Heterocycl. Chem. 11,327-329 (1974)) and 25 ml of isopropanol, and the mixture is stirred at120° C. for 24 hours. The mixture is cooled to 20° C., filtered andwashed with isopropanol, and the filtration product is taken up in 60 mlof methylene chloride. The suspension is stirred at room temperature for15 hours and is then filtered, and the crystallizate is washed withmethylene chloride. In that manner there is obtained the title compound,m.p. 265°-270° C., ¹ H-NMR (DMSO/D₂ O): δ=8.32 (s, 1H); 8.29 (d, 1H);8.19 (s, 1H); 8.04 (d, 1H); 7.88-7.98 (m, 3H); 7.81 (d, 1H); 7.53-7.68(m, 3H); 3.38 (s, 4H).

EXAMPLE 24

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)-imidazoledihydrochloride

Analogously to Example 2, 0.3 g of Raney nickel is added to a mixture of1.0 g (2.13 mmol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)-imidazoledihydrochloride in 120 ml of methanol/water (1:1), and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The reaction mixture is thenfiltered, the filtrate is acidified to pH 3 with 3N methanolichydrochloric acid, and concentration is carried out by evaporation invacuo. Recrystallization of the residue from ethanol with the additionof a small amount of methanol yields the title compound, m.p. >280° C.,¹ H-NMR (DMSO/D₂ O): δ=8.31 (d, 1H); 8.18 (s, 1H); 8.05 (s, 1H);7.92-8.03 (m, 3H); 7.79-7.86 (m, 2H); 7.52-7.69 (m, 3H); 3.35 (s, 4H).

EXAMPLE 25

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazoledihydrochloride

A mixture of 0.837 g (4.079 mmol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.40 g (4.077mmol) of 1,2-diamino-imidazole, 23 ml of isopropanol and 1.33 ml ofconcentrated hydrochloric acid is heated under reflux for 22 hours.Filtration of the hot reaction mixture, washing of the crystallizatewith isopropanol and diethyl ether and drying under a high vacuum yieldthe title compound, m.p. 258°-260° C. (decomp.), ¹ H-NMR (DMSO/D₂ O):δ=8.29 (d, 1H); 7.80 (d, 1H); 7.65 (t, 1H); 7.55 (d, 1H); 7.13 (d, 1H);3.22-3.32 (m 4H).

The starting materials are prepared as follows:

a) N-Benzylidenamino-N'-(2,2-dimethoxy-ethyl)-guanidine

2.88 g (0.06 mol) of sodium hydride dispersion (approximately 50% inoil; Fluka, Buchs, Switzerland) are added in portions over a period of10 minutes, with stirring and with the introduction of nitrogen, to asolution of 8.1 g (0.05 mol) of benzaldehyde guanylhydrazone in 80 ml ofDMF. After 25 minutes stirring at room temperature, 7.1 ml (0.06 mol) ofbromoacetaldehyde dimethylacetal (Aldrich, Buchs, Switzerland; 97%, Cat.no. 24,250-0) are added dropwise to the mixture, which has been cooledin an ice-bath. The reaction mixture is stirred for one hour at roomtemperature and for 20 hours at 55° C., and then concentration byevaporation is carried out in vacuo and the residue is partitionedbetween ethyl acetate and water. The organic phase is washed with waterand brine and is concentrated by evaporation, and the oily residue ispurified by flash chromatography on silica gel having a particle size of0.04-0.063 mm, using ethyl acetate and ethyl acetate/methanol (9:1).Concentration of the product-containing fractions by evaporation yieldsthe title compound in the form of an oil, Rf value=0.80 (silicagel/methylene chloride:methanol:conc. ammonia (40:10:1)), ¹ H-NMR(DMSO): δ=8.07 (s, 1H); 7.67-7.73 (m, 2H); 7.23-7.40 (m, 3H); 5.93 (bs,3H); 4.48 (t, 1H); 3.32 (s, 6H); 3.29 (d, 2H).

b) 1,2-Diamino-imidazole

A mixture of 2.5 g (0.01 mol) ofN-benzylideneamino-N'-(2,2-dimethoxyethyl)guanidine and 50 ml of 2Nhydrochloric acid is heated slowly from 60° C. to 120° C. over a periodof 4 hours, with stirring. The benzaldehyde that is separated off duringthe course of the reaction is removed from the reaction mixture byazeotropic distillation (approximately 2 hours). After making up to theoriginal volume by the addition of water, the reaction mixture is heatedfor a further 8 hours under reflux and is then concentrated byevaporation in vacuo. The resinous residue is dissolved in a mixture of3 ml of methanol and 2.5 ml of 30% sodium hydroxide solution and ispurified by flash chromatography on silica gel having a particle size of0.04-0.063 mm using methylene chloride:methanol (9:1) and methylenechloride:methanol:conc. ammonia (90:10:0.5 and 40:10:1). Concentrationof the product-containing fractions by evaporation yields the titlecompound in the form of an oil, ¹ H-NMR (DMSO): δ=6.60 (s, 1H); 6.38 (s,1H); 5.67 (bs, 2H); 5.54 (bs 2H).

EXAMPLE 26

1- 4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazoledihydrochloride

0.3 g of Raney nickel is added to a solution of 0.8 g (2.33 mmol) of 1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazoledihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation iscarried out at room temperature and under normal pressure until theabsorption of hydrogen has ceased. The filtrate is adjusted to pH 3 witha small amount of 3N methanolic hydrochloric acid and is concentrated byevaporation in vacuo. Recrystallization of the residue frommethanol/water yields the title compound, m.p. >260° C., ¹ H-NMR (D₂ O):δ=8.15 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 7.17 (d, 1H); 6.90 (d, 1H);3.29-3.35 (m, 2H); 3.12-3.18 (m, 2H).

EXAMPLE 27

1-4-(N-HydroxVamidino)-213-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tert-butylphenyl)-imidazoledihydrochloride

0.45 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) isadded, with stirring, to a mixture of 0.307 g (0.0015 mol) of4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.345 g (0.0015mol) of 1,2-diamino-4-(4-tert-butylphenyl)-imidazole (see Ivaschenko A.V. et aL, Khim. Geterotsikl. Soedin. (2), 236-241 (1982)--Englishtranslation: Chem. Heterocycl. Compd. 1982, 185-189) and 7.5 ml ofisopropanol, and the reaction mixture is stirred at 80°-90° C. for 16hours. The reaction mixture is filtered while hot and the filtrationproduct is washed with isopropanol and dried. In that manner there isobtained the title compound, m.p. >250° C., ¹ H-NMR (D₂ O): δ=8.26 (d,1H); 7.86 (s, 1H); 7.75 (d, 1H); 7.6 (m, 3H); 7.47 (d, 2H); 3.28 (s,4H); 1.27 (s, 9H).

EXAMPLE 28

1- 4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneaminol-2-amino-4-(4-tert-butylphenyl)-imidazoledihydrochloride

Analogously to Example 2, approximately 2.0 g of Raney nickel are addedto a solution of 3.9 g (0.0082 mol) of 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tert-butylphenyl)-imidazoledihydrochloride in 400 ml of methanol, and hydrogenation is carried outat room temperature and under normal pressure until the absorption ofhydrogen has ceased. The reaction mixture is then filtered, adjusted topH 4 with a small amount of 2N alcoholic hydrochloric acid andconcentrated to dryness by evaporation. The residue is recrystallizedfrom ethanol, yielding the title compound in the form of the trihydrate,m.p. 250° C. (decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.27 (d, 1H); 7.75-7.92(m, 2H); 7.6 (m, 3H); 7.46 (m, 2H); 3.32 (bs, 4H); 1.27 (s, 9H).

EXAMPLE 29

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-di-hydro-imidazoledihydrochloride

A solution of 0.24 g (0.001 mol) of 4-amidino-2,3-dihydro-1H-inden-1-onehydrochloride and 0.136 g (0.001 mol) of1,2-diamino-4,5-dihydro-imidazole hydrochloride m.p. 245°-246° C.,prepared from the corresponding p-toluenesulfonate salt, see EP 0 327919, Example 12, by ion exchange on ®Amberlite IRA-400 (anion exchangerbased on a styrene/divinylbenzene polymer with quaternary ammoniumgroups in the Cl⁻ form; Fluka, Buchs, Switzerland)! in 3 ml of water isleft to stand at room temperature for 18 hours. The product that hascrystallized out is filtered off with suction and recrystallized fromwater, yielding the title compound (monohydrate), m.p. 280° C.(decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.17 (d, 1H); 7.66 (d, 1H); 7.54 (t,1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m, 2H).

The starting materials are prepared as follows:

a) 4-Thiocarbamoyl-2,3-dihydro-1H-inden-1-one

A solution of 12.1 g (77 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one seeColl. Czechoslov. Chem. Commun. 4, 3227 (1978)! in 220 ml of pyridineand 10.6 ml (77 mmol) of triethylamine is saturated with hydrogensulfide for 3 hours at 40° and is then stirred at the same temperaturefor 16 hours. The reaction mixture is cooled and then concentrated todryness by evaporation, and 300 ml of water are added to the residue.The yellow product that has crystallized out is filtered off withsuction, washed with water, dried and recrystallized from ethyl acetate.In that manner there is obtained the title compound, m.p. 197°(decomp.).

b) 4-Amidino-2,3-dihydro-1H-inden-1-one hydrochloride

10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added at roomtemperature, under argon, to a solution of 9.8 g (51.3 mmol) of4-thiocarbamoyl-2,3-dihydro-1H-inden-1-one in 500 ml of absolutemethylene chloride. After 16 hours, a mixture of 4.2 g of potassiumcarbonate and 4.2 ml of water is added to the reaction solution. Themixture is then stirred briefly and is filtered, and the filtrate iswashed with water. The organic phase is dried over magnesium sulfate,filtered and concentrated by evaporation. The crude ethylthio-iminoether so obtained is dissolved in 160 ml of absolute ethanol; 3.3 g (60mmol) of ammonium chloride are added and the reaction mixture is heatedat reflux for 20 hours. After cooling, the reaction mixture isconcentrated to dryness by evaporation. The title compound is purifiedby chromatography on 1000 ml of ®Amberlite ER-180 (Rohm & Haas,Darmstadt, Germany; ER-180 is a polystyrene-based adsorbate resin whichis used for separating off lipophilic impurities and for decoloring;water as eluant) and is recrystallized from ethanol/diethyl ether, m.p.215°-218° (decomp.).

EXAMPLE 30

1- 5-(Amidino)-tetralin-1-ylideneamino!-2-amino-4,5-dihydro-imidazoledihydrochloride

0.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) isadded, with stirring, to a solution of 0.25 g (0.001 mol) of5-(amidino)-1-tetralone hydrochloride and 0.136 g (0.001 mol) of1,2-diamino-4,5-dihydro-imidazole hydrochloride in 5 ml of iso-propanol,and the mixture is stirred at 80°-90° C. for 16 hours. The reactionmixture is filtered while hot and the filtration product is washed withisopropanol and dried, yielding the title compound, m.p. >220° C.(decomp.), ¹ H-NMR (DMSO/D₂ O): δ=8.15 (d, 1H); 7.67 (d, 1H); 7.55 (t,1H); 4.17 (t, 2H); 3.68 (t, 2H); 3.23 (m, 2H); 3.15 (m, 2H); 1.9 (m,2H).

The starting materials are prepared as follows:

a) 5-Cyano-1-tetralone

0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g(4.4 mmol) of 5-bromo-1-tetralone see J. Org. Chem. 49, 4226 (1984)! in1.3 ml of DMF, and the reaction mixture is stirred at 160° for 6 hours.The reaction mixture is then cooled to 80°, and a solution of 1.6 g ofiron(III) chloride hexahydrate in 2.5 ml of water and 0.44 ml ofconcentrated hydrochloric acid is added. Stirring is continued for 45minutes, the reaction mixture is cooled and diluted with water, andextraction is carried out with toluene. The organic phase is washed withwater, dried over magnesium sulfate, filtered and concentrated byevaporation. In that manner there is obtained the title compound in theform of yellow-orange crystals, IR (CH₂ Cl₂): 2220, 1690 cm⁻¹ ; ¹ H-NMR(CDCl₃): δ=8.26 (q,1H); 7.81 (q,1H); 7.43 (t,1H); 3.21 (t,2H); 2.72(t,2H); 2.23 (m,2H).

b) 5-Thiocarbamoyl-1-tetralone

Analogously to Example 29a), 10.6 g (62 mmol) of 5-cyano-l-tetralone in200 ml of pyridine and 8.6 ml of triethylamine are treated with hydrogensulfide and worked up. There is thus obtained the title compound in theform of yellow crystals, m.p. 200°-205°.

c) 5-Amidino-1-tetralone hydrochloride

Analogously to Example 29b), 8.6 g (42 mmol) of5-thiocarbamoyl-1-tetralone are treated with 8.8 g (44 mmol) oftriethyloxonium tetrafluoroborate and 2.6 g (49 mmol) of ammoniumchloride. There is thus obtained the title compound in the form ofslightly pink-colored crystals, MS (FAB): (M+H)⁺ =189.

EXAMPLE 31

1- 5-(Amidino)-tetralin-1-ylideneamino!-2-amino-4-phenyl-imidazoledi-hydrochloride

Analogously to Example 3, 5-(amnidino)-1-tetralone hydrochloride isreacted with 1,2-di-amino-4-phenyl-imidazole, yielding the titlecompound. M.p. >240° C. (decomp.), ¹ H-NMR (DMSO/D₂ O) δ=8.54 (d, 1H);7.6-7.8 (m, 4H); 7.3-7.58 (M, 5H); 2.96 (m, 2H); 2.88 (m, 2H); 1.9 (m,2H).

EXAMPLE 32

1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazoledihydrochloride

A mixture of 0.406 g (0.0019 mol) of 4-cyano-2,3-dihydro-1H-inden-1-one2'-amidino-hydrazone (prepared from the HCl salt in aqueous solutionwith NaOH) and 0.19 g (0.0009 mol) of phenacyl bromide (Aldrich, Buchs,Switzerland; Cat. No. 11,583-5) in 40 ml of ethanol is boiled underreflux for 4 hours. The reaction mixture is filtered while hot and thefiltration product is washed with ethanol and dried, yielding 1-4-cyano-2,3-di-hydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazole,MS (FAB): (M+H)⁺ =314, ¹ H-NMR (DMSO): δ=8.32 (d, 1H); 7.94 (d, 1H);7.76 (m, 3H); 7.56 (t, 1H); 7.32 (m, 2H); 7.16 (t, 1H); 6.12 (s, 2H);3.35 (bs, 4H).

That intermediate is maintained under reflux in ethanol for 4 hours withequivalent amounts of hydroxylamine hydrochloride and sodium carbonate,the title compound being obtained after working up with hydrochloricacid (for physical data see Example 1).

The starting material is prepared as follows:

a) 4-Cyano-2,3-dihydro-1H-inden-1-one 2-amidinohydrazone hydrochloride

314 mg (2 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one are dissolved in20 ml of methanol, a solution of 272 mg (2 mmol) of aminoguanidinehydrogen carbonate in 9 ml of water and 1 ml of 2N hydrochloric acid areadded thereto and the mixture is stirred at reflux for 4 days. Aftercooling, the reaction mixture is concentrated to dryness by evaporationand the residue is crystallized from water. There is thus obtained thetitle compound, m.p. >230° C.; ¹ H-NMR (DMSO-d₆ /D₂ O): δ=8.16 (d,1H);7.9 (d,1H); 7.55 (t,1H); 3.28 (m,2H); 2.9 (m,2H); IR(Nujol): 2190 cm⁻¹(CN).

EXAMPLE 33

1-(3-Amidinobenzylideneamino)-2-amino-4-phenyl-imidazole dihydrochloride

Analogously to Example 31, 3-amidinobenzaldehyde hydrochloride isreacted with 1,2-di-amino-4-phenyl-imidazole, yielding the titlecompound.

The starting material is prepared as follows:

a) Ethyl-3-formylbenzimidate hydrochloride (3-formyl-benzimide acidethyl ester chloride):

59.7 ml (1.025 mol) of absolute ethanol are added to a solution of 86.7g (0.662 mol) of 3-cyanobenzaldehyde (Aldrich, Buchs, Switzerland, Cat.No. 14,625-0) in 530 ml of absolute diethyl ether and the reactionsolution is cooled to 0° C. The reaction solution is saturated with dryhydrochloric acid gas and then left to stand at 0° C. for 6 days. When afine precipitate has been filtered off, 1 liter of diethyl ether isadded to the reaction solution. The title compound crystallizes out,m.p. 126°-128° C. (with foaming).

b) 3-Amidinobenzaldehyde hydrochloride

250 ml of absolute ethanol and 250 ml of saturated ethanolic ammoniasolution are added to 21.3 g (0.1 mol) of the imino ether from Example33a) and the mixture is heated at 70° C. for 3 hours. After cooling, theethanol is evaporated off and the residue, which corresponds to thetitle compound in crude form, is reacted further directly.

EXAMPLE 34

1-(α-Methyl-3-amidinobenzylideneamino)-2-amino-4-phenyl-imidazoledi-hydrochloride

Analogously to Example 3, 3-amidinoacetophenone hydrochloride is reactedwith 1,2-di-amino-4-phenyl-imidazole, yielding the title compound.

The starting material is prepared as follows:

a) Ethyl-3-acetylbenzimidate hydrochloride (3-acetyl-benzimide acidethyl ester hydrochloride)

A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile (Aldrich, Buchs,Switzerland; Cat. No. 29,221-4) in 150 ml of diethyl ether and 4.5 ml ofethanol is saturated at 0° C. with dry hydrochloric acid gas and thenleft to stand at 0° C. for 2 days. The product that has crystallized outis filtered off and the title compound is obtained afterrecrystallization from ethanol/diethyl ether, m.p. 110° C. (decomp.).

b) 3-Amidinoacetophenone hydrochloride

11.4 g of the title compound from Example 34a), 200 ml of ethanol and125 ml of saturated ethanolic ammonia solution are boiled at reflux for6 hours. After cooling, the reaction mixture is concentrated byevaporation, and the residue is dissolved in 4N hydrochloric acid,washed with diethyl ether and concentrated to dryness by evaporation.The resulting crude product (title compound) is used further directly.

The following compounds are prepared analogously to one of the methodsdescribed in this Application (Examples 35 to 44)

EXAMPLE 35

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-methoxyphenyl)-imidazoledihydrochloride

EXAMPLE 36

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4,5-tri-methoxyphenyl)-imidazoledihydrochloride

EXAMPLE 37

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-methoxyphenyl)-imidazoledihydrochloride

EXAMPLE 38

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-methylphenyl)-imidazoledihydrochloride

EXAMPLE 39

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-methylphenyl)-imidazoledihydrochloride

EXAMPLE 40

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-di-methylphenyl)-imidazoledihydrochloride

EXAMPLE 41

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-chlorophenyl)-imidazoledihydrochloride

EXAMPLE 42

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-chlorophenyl)-imidazoledihydrochloride

EXAMPLE 43

1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-di-chlorophenyl)-imidazoledihydrochloride

EXAMPLE 44

1-14-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-(tert-butyl)phenyl)-imidazoledihydrochloride

EXAMPLE 45

Capsules

Capsules containing 1 g of active ingredient, i.e. a compound of formulaI according to any one of Examples 1 to 34, are prepared as follows:

    ______________________________________                                        Composition (for 1250 capsules):                                              ______________________________________                                        active ingredient        1250 g                                               talc                     180 g                                                wheat starch             120 g                                                magnesium stearate       80 g                                                 lactose                  20 g                                                 ______________________________________                                    

The pulverulent substances are forced through a sieve of 0.6 mm meshsize and mixed. 1.32 g portions of the mixture are introduced intogelatin capsules using a capsule-filling machine.

EXAMPLE 46

Tablets

10000 tablets, each comprising 5 mg of active ingredient, i.e. one ofthe compounds of formula I prepared in Examples 1 to 34, are prepared:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient     50.00 g                                                 lactose               2535.00 g                                               corn starch           125.00 g                                                polyethylene glycol 6.000                                                                           150.00 g                                                magnesium stearate    40.00 g                                                 purified water        quantum satis                                           ______________________________________                                    

Method: All the pulverulent constituents are forced through a sieve of0.6 mm mesh size. Then the active ingredient, the lactose, the magnesiumstearate and half the starch are mixed in a suitable mixer. The otherhalf of the starch is suspended in 65 ml of water and the resultingsuspension is added to a boiling solution of the polyethylene glycol in260 ml of water. The paste that is formed is added to the powder mixtureand granulated, if necessary with the addition of more water. Thegranules are dried overnight at 35° C., forced through a sieve of 1.2 mmmesh size and compressed to form tablets having a breaking notch.

EXAMPLE 47

Infusion or injection solutions

Infusion or injection solutions comprising 100 mg of active ingredientdissolved in 5 ml of aqueous 5% D-glucose solution are prepared. Theactive ingredient used is one of the compounds from Examples 1 to 34.The solutions are introduced into vials.

EXAMPLE 48

Dry vials

Dry vials are parepared by lyophilising solutions prepared in Example 37of one of the active ingredients mentioned therein.

EXAMPLE 49

Inhibition of S-adenosylmethionine decarboxylase (SAMDC)

Using the method of A. E. Pegg and H. S. Poso (see Methods Enzymol. 94,234-239 (1983)) mentioned hereinbefore, the following IC₅₀ values areobtained for the inhibition of the enzyme SAMDC for the compounds offormula I mentioned below:

    ______________________________________                                        Title compound of formula I                                                   from Example       IC.sub.50 (mM)                                             ______________________________________                                        2                  2                                                          4                  3.6                                                        6                  8.4                                                        8                  8.9                                                        10                 4.2                                                        12                 6.7                                                        14                 3.4                                                        16                 4.0                                                        18                 6.1                                                        20                 3.4                                                        22                 11                                                         24                 7.5                                                        28                 5.4                                                        ______________________________________                                    

EXAMPLE 50

Inhibition of the growth of human T24 bladder carcinoma cells:

The inhibition of the growth of human T24 bladder carcinoma cells ismeasured using the method mentioned hereinbefore. The following IC₅₀values (concentration of the test compound at half the maximuminhibition) are determined using the following Examples:

    ______________________________________                                        Title compound of formula I                                                   from Example       IC.sub.50 (mM)                                             ______________________________________                                        2                  1.16                                                       4                  2                                                          6                  1.2                                                        8                  1.6                                                        10                 2.6                                                        12                 1.55                                                       14                 1.12                                                       16                 2.70                                                       18                 1.5                                                        20                 0.28                                                       22                 0.44                                                       24                 2.46                                                       26                 2.15                                                       28                 0.23                                                       ______________________________________                                    

EXAMPLE 51

Inhibition of the growth of T24 bladder carcinoma cells in vivo (nudemouse)

Using the method mentioned hereinbefore (see also Regenass et al.,Cancer Res. 54, 3210-3217 (1974)), the compound of Example 2 of thepresent Application is administered in accordance with the followingtreatment scheme to BALB/c nude mice with transplanted human T24 bladdercell carcinomas: The compound is administered p.o. (50, 25 and 12.5mg/kg) or i.p. (12.5, 6.25 and 3.13 mg/kg). The compound is dissolved indistilled water and diluted with 3 volumes of 0.9% NaCl (w/v) in water.

As shown in the following Table, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazoledihydrochloride inhibits the growth of T24 bladder carcinoma cells bothon oral and on intraperitoneal administration. The dose-dependence ofthe action is observed. The maximum tolerated dose is >500 mg/kg in thecase of p.o. administration and 125 mg/kg in the case of i.p.administration.

Inhibition of T24 tumor growth:

    ______________________________________                                                             T/C (%)* on                                              Title compound from Example 2                                                                      administration                                           (mg/kg)              i.p.    p.o.                                             ______________________________________                                        0 (control)          100     100                                              3.13                 34      n.d.                                             6.25                 22      n.d.                                             12.5                 16      68                                               25                   n.d.    47                                               50                   n.d.    31                                               ______________________________________                                         (n.d. = not determined)                                                       *average for 6 animals                                                   

What is claimed is:
 1. A compound of formula I ##STR21## wherein R₁ ishydroxy or hydrogen;the radicals R₂, R₂ ' and R₂ " are eachindependently of the others hydrogen or a substituent selected fromlower alkyl, halo-lower alkyl having one or more halogen atoms, C₃ -C₈cycloalkyl, phenyl-lower alkyl, hydroxy, lower alkoxy, phenyl-loweralkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, halogen, amino,N-lower alkylamino, N,N-di-(lower alkyl)amino, lower alkanoylamino,benzoylamino, nitro, lower alkanoyl, benzoyl, carboxy, loweralkoxycarbonyl, 1 -phenyl-lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di(lower alkyl)carbamoyl, N-phenylcarbamoyl, cyano,mercapto, lower alkylthio, lower alkanesulfonyl, sulfamoyl, N-loweralkylsulfamoyl and N,N-di (lower alkyl)sulfamoyl; eitherR₃ is hydrogenand R₄ is hydrogen or lower alkyl, orR₃ and R₄ together form a divalentradical of the formula --(CH₂)n--wherein n is 2 or 3; R₅ and R₆ are eachindependently of the other hydrogen, lower alkyl; or phenyl or naphthyleach of which is unsubstituted or mono- to tri-substituted, wherein thesubstituents are selected independently of one another from the groupconsisting of lower alkyl, phenyl, naphthyl, lower alkoxy, hydroxy,lower alkanoyloxy, nitro, amino, halogen, halo-lower alkyl, caboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di(loweralkyl)carbamoyl, cyano, lower alkanoyl, phenyl- or naphthyl-carbonyl,lower alkanesulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-loweralkyl-sulfamoyl; and either R₇ and R₈ are each hydrogen, or R₇ and R₈together form a bond; a tautomer thereof, provided that at least onetautomerisable group is present; or a salt thereof.
 2. A compound offormula I according to claim 1 whereinR₁ is hydroxy or hydrogen; theradicals R₂, R₂ ' and R₂ " are each independently of the others hydrogenor a substituent selected from lower alkyl, halo-lower alkyl having oneor more halogen atoms, C₃ -C₈ cycloalkyl, phenyl-lowe:r alkyl, hydroxy,lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy,benzoyloxy, halogen, amino, N-lower alkylamino, N,N-di-(loweralkyl)amino, lower alkanoylamino, benzoylamino, nitro, lower alkanoyl,benzoyl, carboxy, lower alkoxycarbonyl, 1-phenyl-lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di(lower alkyl)carbamoyl,N-phenylcarbamoyl, cyano, mercapto, lower alkylthio, loweralkanesulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-(loweralkyl)sulfamoyl; eitherR₃ is hydrogen and R₄ is hydrogen or lower alkyl,orR₃ and R₄ together form a divalent radical of the formula --(CH₂)--wherein n is 2 or 3; R₅ and R₆ are each independently of the otherhydrogen, lower alkyl; or phenyl or naphthyl each of which isunsubstituted or mono- or di-substituted, wherein the substituents areselected independently of one another from the group consisting of loweralkyl, phenyl, naphthyl, lower alkoxy, hydroxy, lower alkanoyloxy,nitro, amino, halogen, halo-lower alkyl, carboxy, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di(lower alkyl)carbamoyl, cyano,lower alkanoyl, phenyl- or naphthyl-carbonyl, lower alkanesulfonyl,sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower alkyl-sulfamoyl;andeither R₇ and R₈ are each hydrogen, or R₇ and R₈ together form abond; a tautomer thereof, provided that at least one tautomerisablegroup is present; or a salt thereof.
 3. A compound of formula Iaccording to claim 1 whereinR₁ is hydroxy or hydrogen; R₂, R₂ ' and R₂ "are each hydrogen; eitherR₃ is hydrogen and R₄ is hydrogen or loweralkyl, or R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --; R₅ ishydrogen, lower alkyl; or naphthyl or phenyl each of which isunsubstituted or substituted by one or two radicals selected from loweralkoxy, halogen, lower alkyl and phenyl; R₆ is hydrogen; and either R₇and R₈ are each hydrogen, or R₇ and R₈ together form a bond; a tautomerthereof, provided that at least one tautomerisable group is present; ora salt thereof.
 4. A compound of formula I according to claim 1whereinR₁ is hydroxy or hydrogen; the radicals R₂, R₂ ' and R₂ " areeach hydrogen; eitherR₃ is hydrogen and R₄ is hydrogen or lower alkyl,or R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --; R₅ is hydrogen,lower alkyl, phenyl, 2-, 3- or 4-lower alkoxyphenyl, 2,5-di-loweralkoxy-phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-lower alkylphenyl,4-biphenylyl, or 1- or 2-naphthyl; R₆ is hydrogen; and either R₇ and R₈are each hydrogen, or R₇ and R₈ together form a bond; or a salt thereof.5. A compound of formula I according to claim 1 whereinR₁, R₂, R₂ ' andR₂ " are each hydrogen; eitherR₃ is hydrogen and R₄ is hydrogen ormethyl, or R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --; R₅ ishydrogen, ethyl, phenyl, 2-, 3- or 4-methoxyphenyl, 2,5-dimethoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-biphenylyl or2-naphthyl; R₆ is hydrogen; and either R₇ and R₈ are each hydrogen, orR₇ and R₈ together form a bond; or a salt thereof.
 6. A compound offormula I according to any one of claim 1 wherein R₁ is hydrogen and theother radicals are as defined; a tautomer thereof, provided that atleast one tautomerisable group is present, or a salt thereof.
 7. Acompound of formula I according to any one of claim 1 wherein R₅, R₆, R₇and R₈ are each hydrogen and the other radicals are as defined; atautomer thereof, provided that at least one tautomerisable group ispresent, or a salt thereof.
 8. A compound of formula I according to anyone of claim 1 wherein R₃ and R₄ together are --(CH₂)₃ -- or --(CH₂)₂ --and the other radicals are as defined; a tautomer thereof, provided thatat least one tautomerisable group is present, or a salt thereof.
 9. Acompound of formula I according to claim 1 whereinR₁, R₂, R₂ ' and R₂ "are each hydrogen; R₃ and R₄ together are --(CH₂)₂ -- or --(CH₂)₃ --; R₅is 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl,3,4-dimethyl-phenyl, 3,5-dimethylphenyl, 2,4-dimethylphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl or3,5-di(tert-butyl)phenyl; R₆ is hydrogen; and R₇ and R₈ together form abond; or a salt thereof.
 10. 1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazoleof formula I according to claim 1, or a pharmaceutically acceptable saltthereof.
 11. A compound of formula I according to claim 1, selected fromthe following compounds: 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxyphenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-methoxyphenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-dimethoxy-phenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-chlorophenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-l-ylideneamino!-2-amino-4-(4-tolyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluorophenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-biphenylyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)-imidazole,1- 4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tert-butyl-phenyl)-imidazole,1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazole,1- 5-(amidino)-tetralin-1-ylideneamino!-2-amino-4,5-dihydro-imidazole,1- 5-(amidino)-tetralin-1 -ylideneamino!-2-amino-4-phenyl-imidazole,1-(3-amidinobenzylideneamino)-2-amino-4-phenyl-imidazole and1-(α-methvl-3-amidinobenzylideneamino)-2-amino-4-phenyl-imidazole; or apharmaceutically acceptable salt thereof.
 12. A compound of formula Iaccording to claim 1, selected from the compounds1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxy-phenyl)-imidazole,1- 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-methoxy-phenyl)-imidazole, 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-di-methoxyphenyl)-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3-methoxy-phenyl)-imnidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-chloro-phenyl)-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tolyl)-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluoro-phenyl)-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-bi-phenylyl)-imidazole,1- 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)-imidazole, 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazole,1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tert-butyl-phenyl)-imidazoleand 1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazole;or a pharmaceutically acceptable salt thereof.
 13. A compound of formulaI according to claim 1, selected from the following compounds:1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-dimethoxyphenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4,5-trimethoxy-phenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-dimethoxyphenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-dimethylphenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-dimethylphenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-dimethylphenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-dichlorophenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-dichlorophenyl-imidazoledihydrochloride, 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-dichlorophenyl-imidazoledihydrochloride and 1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di(tert-butyl)-phenyl-imidazole-dihydrochloride;or a pharmaceutically acceptable salt thereof.
 14. A process for thepreparation of a compound of formula I according to claim 1, a salt or atautomer thereof, which process comprisesa) reacting a compound offormula II ##STR22## wherein W₁ is functionally modified carboxy and theother radicals are as defined for compounds of formula I, or a saltthereof, with hydroxyl ami-ne or ammonia of formula III

    R.sub.1 --NH.sub.2                                         (III),

wherein R₁ is hydrogren or hydroxy, or with a salt thereof, functionalgroups in the starting materials that are not intended to participate inthe reaction being, in protected form, and removing any protectinggroups that are present; or b) reacting a hydroxyimino compound offormula IV ##STR23## wherein the radicals are as defined for compoundsof formula I, or a salt thereof, with an aminoimidazole of formula V##STR24## wherein the radicals are as defined for compounds of formulaI, or with a salt thereof, functional groups in the starting materialsthat are not intended to participate in the reaction being in protectedform, and removing any protecting groups that are present; or c) for thepreparation of a compound of formula I wherein R₁ is hydrogen and theother radicals are as defined, reacting an oxo compound of formula VI##STR25## or a reactive derivative thereof, wherein the radicals are asdefined for compounds of formula I, or a salt thereof, with an aminoimidazole of formula V ##STR26## wherein the radicals are as defined forcompounds of formula I, or with a salt thereof, functional groups in thestarting materials that are not intended to participate in the reactionbeing in protected form, and removing any protecting groups that arepresent; or converting a compound of formula I obtained according to oneof processes a), b) or c) into a different compound of formula Iconverting a resulting salt of a compound of formula I into the freecompound, converting into a salt a free compound of formula I havingsalt-forming properties that has been obtained directly or according tothe last-mentioned step from a different salt, and/or, separating aresulting mixture of isomers of compounds of formula I into individualisomers.
 15. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a therapeutically effective amount ofa compound according to claim 1, or a pharmaceutically acceptable saltthereof.
 16. A method of treating pathological conditions which areresponsive to the inhibition of the enzyme S-adenosylmethioninedecarboxylase comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 17. A methodaccording to claim 16 for treating a proliferative disease.
 18. A methodaccording to claim 16 for treating a protozoal infection.